review

Neuropsychiatr (2021) 35:113–134

https://doi.org/10.1007/s40211-021-00395-9

Practitioner’s review: medication for children and

adolescents with autism spectrum disorder (ASD) and
comorbid conditions
Christian Popow · Susanne Ohmann · Paul Plener

Received: 12 January 2021 / Accepted: 15 May 2021 / Published online: 23 June 2021
© The Author(s) 2021

Abstract Alleviating the multiple problems of children und Elterntraining nicht immer aus, insbesondere bei
with autism spectrum disorder (ASD) and its comor- Menschen mit geistiger Behinderung (GB) und mul-
bid conditions presents major challenges for the af- tiplen Komorbiditäten. Darüber hinaus steht für viele
fected children, parents, and therapists. Because of Patienten keine strukturierte Therapie zur Verfügung,
a complex psychopathology, structured therapy and und häufig ist pharmakologische Unterstützung er-
parent training are not always sufficient, especially forderlich, insbesondere bei Kindern, bei denen eine
for those patients with intellectual disability (ID) and Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung und
multiple comorbidities. Moreover, structured therapy oppositionelle Trotz-, Verhaltens- oder Schlafstörun-
is not available for a large number of patients, and gen hinzukommen.
pharmacological support is often needed, especially
in those children with additional attention deficit/ Schlüsselwörter Autismus-Spektrum-Störung ·
hyperactivity and oppositional defiant, conduct, and ADHS · Kinder und Jugendliche · Pharmakotherapie
sleep disorders.
Introduction
Keywords Autism spectrum disorder · ADHD ·
Children and adolescents · Pharmacotherapy Autism spectrum disorder (ASD) is a common [73],
complex, genetically based, disabling disorder [15]
Practitioner Review: Medikamentöse that needs specific knowledge and parenting skills
Behandlung von Kindern und Jugendlichen mit [165] and burdensome, costly treatment. The com-
Autismus-Spektrum-Störung (ASS) und plex clinical picture is characterized in ICD-11 6A02
Komorbiditäten [320] by
 Persistent deficits in the ability to initiate and sus-
Zusammenfassung Die Linderung der vielfältigen tain reciprocal social interaction and social commu-
Probleme von Kindern mit Autismus-Spektrum-Stö- nication,
rung (ASS) und ihrer Begleiterkrankungen stellt für  A range of restricted, repetitive, and inflexible pat-
die betroffenen Kinder, Eltern und Therapeuten eine terns of behavior and interests, and
große Herausforderung dar. Aufgrund einer komple-  A high prevalence of intellectual disability, language
xen Psychopathologie reichen strukturierte Therapie impairments, and other comorbid disorders

and a number of comorbid conditions such as at-

C. Popow () · S. Ohmann · P. Plener tention deficit/hyperactivity disorder (ADHD), sleep
Dept. Child and Adolescent Psychiatry, Medical University disorders, convulsions, oppositional defiant disorder
of Vienna, Waehringer Guertel 18–20, 1090 Vienna, Austria
(ODD), anxieties, obsessions and compulsions (OCD),
[email protected]
depression, and numerous other symptoms and con-
S. Ohmann ditions that are discussed as to whether they represent
[email protected] “core” or comorbid problems [281]. These conditions
P. Plener differ in symptomatology, prevalence, and treatability
[email protected] from those of normally developing children. These

K Practitioner’s review: medication for children and adolescents with autism spectrum disorder (ASD) and. . . 113
 review

Table 1 Abbreviations
Abbrev. Definition Abbrev. Definition
ABA Applied behavioral analysis IQ Intelligence (Quotient)
ACTH Adrenocorticotropic hormone, corticotropin LGS Lennox–Gastaut syndrome
AD Antidepressant LKS Landau–Kleffner syndrome
AD MAOI Monoamino oxidase inhibitor
ADHD Attention deficit/hyperactivity syndrome MPEP 2-methyl-6- (phenylethynyl)pyridine
BD Bipolar disorder MT1 Melatonin 1 (receptor)
ASD Autism spectrum disorder NDRI Norepinephrine-dopamine reuptake inhibitor
BPD Borderline personality disorder NMDA N-methyl-D-aspartate
CBT Cognitive behavioral therapy OCD Obsessive compulsive disorder
CSWS Continuous spike waves during slow-wave sleep ODD/CD Oppositional defiant disorder/conduct disorder
DSM-5 Diagnostic and Statistic Manual for Mental Disorders, PE Partial epilepsy
5th edition
DRESS Drug rash with eosinophilia and systemic symptoms PECS Picture exchange communication system
EF Executive functions (functioning) REM sleep Rapid eye movement sleep
ESES Electrical status epilepticus during slow-wave sleep RLS Restless legs syndrome
FDA Food and Drug Administration SGA Second generation antipsychotic
FGA First generation antipsychotic SSRI Selective serotonin reuptake inhibitor
FXS Fragile X syndrome SNRI Selective serotonin and norepinephrine reuptake inhibitor
GABA Gamma-amino-butyric acid SE Side effects
GAD Generalized anxiety disorder t 1/2 Half life
CBT Cognitive behavioral therapy TCA Tricyclic antidepressant
ICD International Classification of Diseases TCM Traditional Chinese medicine
ID Intellectual disability TEACCH Treatment and education of autistic and related communication handi-
capped children
IGF-1 Insulin-like growth factor – 1 VPS Valproic acid

differences, partly related to the reduced flexibility of the necessary means. Less affected children will
(for change), partly to genetic and social conditions, present with flexibility problems and may easily be
may render therapy and its prognosis difficult, and overburdened with social problems [166]. Additional
will increase the impairments of self-worth/self-effi- challenges may be caused by comorbid conditions
cacy and the tendency for depression in the children like ADHD, dysexecutive problems, depression, anxi-
on the spectrum. Comorbid conditions also seem to ety disorders, or seizures [10, 18, 24, 38, 105, 106, 187,
contribute to the increased mortality of children with 201, 281] (Table 2 [187, 223, 281]). Therapy should aim
ASD [304]. at attaining autonomy, flexibility, social competence,
ASD comprises persons with a very low functional an educational level that is appropriate to the individ-
level up to a normal or even supranormal level with ual intellectual capacity of the child, and provide the
relatively low impairment. The disorder may not be basis for a self-determined and socially integrated life.
cured but largely ameliorated by therapy and guided “Conventional” pharmacotherapy is targeted to
intrafamilial support [36, 165]. Especially in children reduce inappropriate behavior and the associated
with a low functional level, structured behavioral ther- burden for family, school, and the social environ-
apies [178] such as ABA1 and its variants, TEACCH2 or ment, to limit inattention, impulsivity, and hyperac-
PECS3 have been proven to be beneficial. Therapeutic tivity associated with ADHD, and to reduce the risk
success will depend on the level of impairment, the in- of seizures. Up to two-thirds of children with ASD are
trafamilial and peer relation support, the availability, treated with psychotropics, and a third with multiple
quality and quantity of therapeutic support [183, 192], drugs [92, 156, 288]. Newer trends aim at improving
the age at diagnosis [86, 119, 229, 263, 299], the types social communication [21] or at transferring exper-
and number of comorbid conditions, and the financial imental therapies into real life [81, 171]. Examples
support provided by the state or the social insurance, include improving the imbalance between excitatory
because an individual family will usually not dispose (glutamatergic) and inhibitory (GABA-ergic) neuro-
transmission [180, 216] or synaptic plasticity [34].
Among the most promising candidate substances are
1 applied behavioral analysis [209]. [171], NMDA4 antagonists [33], memantine [139], and
2 Treatment and Education of Autistic and related Communica-
tion Handicapped Children [211].
3 Picture Exchange Communication System [89]. 4 N-methyl-D-aspartate.

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Table 2 ASD: relevant comorbid disorders standing during the writing process. This added to 965
Disorders Normotypic Chil- ASD Chil- References references of which 325 were cited in this article, de-
dren % dren % pending on their subjectively estimated significance5,
Anxiety disorders 20–40 11–84 [281] and aiming at not overloading the chapter with cita-
Sensory integration/EF 7.5–15 > 75 [126, 198] tions (see Fig. 1). The relationship between reviews
Sleep disorder 22–32 40–80 [175] and meta-analyses and original papers in the cited
ADHD 5–7 30–75 [10, 58, 266] references was 1 : 3.
ODD/CD 30–90 [264]
Intellectual disability 2–3 25–70 [163] Pharmacotherapy of ASD
OCD 2.5 8–37 [187]
In the following, we will discuss the various groups
Epilepsy 1–3 20–34 [24, 105, 261]
of pharmaceuticals used in children and adolescents
Depression/BPD 2–3 11–20 [161, 201] with ASD, namely antipsychotics, antidepressants,
Tic disorder 1–2 9–20 [260] and anticonvulsants.
Central auditory processing 2–5 ? [16]
disorder
Antipsychotics

d-Cycloserine [68, 214], the GABA agonists, baclofen Antipsychotics influence dopamine neurotransmis-
or arbaclofen [77, 130], oxytocin [17, 21, 47, 113, 313], sion, act sedating in lower, antipsychotic in medium,
vasopressin [235] or balovaptan [27], and insulin-like and narcotic in high doses. First generation an-
growth factors (IGF-I) [44, 301]. Among these, only the tipsychotics (FGA), especially haloperidol, have been
binding hormone oxytocin has gained widespread at- shown to influence stereotypic and hyperactive be-
tention, stimulating a considerable number of clinical havior, to reduce temper tantrums and social isola-
studies, although with inconsistent results [228]. tion [9]. FGAs should no longer be used because of
In order to improve the multiple medical, so- an inappropriate risk–benefit ratio related to cogni-
cial, behavioral, learning, or sleep-related problems, tive as well as early and late (e.g., dyskinetic) side
a number of drugs have been recommended and effects. As an alternative, second generation antipsy-
studied in clinical trials [241]. In addition, a number chotics (SGAs), especially risperidone, aripiprazole,
of experimental therapies, such as diets and brain and quetiapine, are substances of choice for treating
extracts, were tried, most of them without any clinical aggression, self-injuring behavior, temper tantrums,
evidence. Because the individual reaction to phar- withdrawal, tics, and rituals.
macotherapy varies considerably [28], individualized This is also true for the SGA clozapine because of
treatment is mandatory [218]. We, therefore, per- its dangerous hematologic side effects [152]. As an
formed a systematic review of the current literature, alternative, SGAs, especially risperidone, aripiprazole,
aiming at providing an overview on recommended and quetiapine, are substances of choice for treating
pharmacotherapy for ASD and its most important aggression, self injuring behavior, temper tantrums,
comorbid disorders. The review is divided into three withdrawal, tics and rituals [35, 43, 62, 68, 103, 122,
sections: 153, 170, 221, 231, 241, 249, 262, 272, 290, 295, 319].
1. Pharmacologic agents Other SGAs (such as asenapine and iloperidone) may
2. Therapy for common problems of ASD and comor- also be used off-label but do not offer advantages
bid disorders [326]. Positive effects should be balanced against
3. Other substances, supplementary and alternative (metabolic, endocrine, neurologic, and cardiac) side
therapies. effects [61, 273]. Therefore, mainly low-dose applica-
tion should be tried. Recommended dosages and spe-
Methods cific features are listed in Table 4. Adding topiramate
to risperidone therapy was more effective on overall
We searched the database PubMed/Medline for the behavior when compared to risperidone monother-
following terms: autism AND pharmacotherapy OR apy [257]. A potential adverse effect of topiramate on
medication, and retrieved 4.248 citations. Restricting language development [227] has, nevertheless, to be
the period covered to the years 2000–2019 and the lan- considered.
guage to English OR French OR German; 3.607 cita-
tions remained, including 1120 reviews. Selecting rel- Antidepressants
evant titles, primarily taking into account the contents
and quality of the papers, and secondarily the au- In normally developing children, selective serotonin
thors, publication media (impact factor), and date (se- antagonists (SSRIs) are effective against depressive
lecting newer references), 223 remained. These were
carefully studied in detail and supplemented by 742 5 Again, selecting more carefully performed studies, more recent,
additional relevant articles retrieved by specific topic often cited papers, and preferring reviews, if available, over orig-
searches that were considered important for under- inal studies.

K Practitioner’s review: medication for children and adolescents with autism spectrum disorder (ASD) and. . . 115
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Fig. 1 Processing of records

symptoms with substance-related differences in ef- nificant weight gain [143]. Studies in autistic chil-
fectivity and side effects. SSRIs also act against anxiety dren are scarce (e.g., [243]), and long-term studies are
disorders in lower dosages and against OCD in higher not available. Mirtazapine, therefore, should not be
dosages, compared to the treatment of depression. In used or only used for a limited period and in low
children with ASD, SSRIs are widely prescribed, but doses. Clomipramine and tricyclic antidepressants
their therapeutic effect is less evident [319]. Other should only be used with care because of their severe
AD agents, such as MAOIs, mirtazapine, hypericum, side effects, and duloxetine and pregabaline have not
etc., also seem to produce only little effect, possibly been systematically studied in children and adoles-
because of elevated peripheral serotonin blood levels cents with ASD.
in a number of children and adolescents with ASD In summary, although AD medication, especially
[100, 232, 309, 319]. SSRIs, is widely prescribed in children and adoles-
A few studies suggest improvements of repetitive cents, its effectiveness is limited to not evident in
and stereotypic behavior with AD therapy in children children with ASD, and side effects may be more ex-
with ASD [221], although this was not reported by aggerated in these patients. Therefore, the use of ADs
King et al. [168] or Williams et al. [319]. Side ef- in ASD can generally not be recommended. Because
fects of SSRIs usually are mild but may be exagger- of their widespread use, pharmacologic data on AD
ated in children with ASD, especially when children medication are nevertheless summarized in Table 5.
are restless and agitated [173]. Bupropion, a NDRI6
acts like a stimulant, may create dependence, and Anticonvulsants
should not be used in adolescents. Mirtazapine [243], Anticonvulsants may be used to treat epilepsies, bipo-
a tricyclic AD, has modest antidepressant effects and lar disorders, and externalizing behavioral problems7.
further acts as a sedative and hypnotic agent by stim- Anticonvulsant treatment of children with ASD [83,
ulating H1 receptors but is slowly eliminated (t 1/2 133, 261], like in other patients with convulsions, de-
37 h), strongly increases appetite, and leads to sig-

6 norepinephrine and dopamine reuptake inhibitor. 7 With inconsistent results [129, 137].

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Table 3 ASD Symptoms, comorbid disorders and (off-la- concluded that individualized treatment is manda-
bel) pharmacotherapy tory. Table 3 summarizes the medical indications and
Symptoms Available drugs available drugs.
Behavioral problems, restlessness, tem- Antipsychotics, (anticonvulsants)
per tantrums, self-injuring behavior ADHD
Social problems Oxytocin, D-cycloserin, meman- ASD and ADHD share genetic, neurophysiological,
tine (experimental)
and clinical similarities [10, 181]. Both disorders
Sleeping problems Melatonin, antipsychotics, anti- affect attention, flexibility, planning, and response
histaminics
inhibition, have a high heritability, early onset, over-
ADHD Atomoxetin, methylphenidate,
amphetamines, (guanfacine ER) lapping comorbidities, and prevail in males [50, 58].
Hans Asperger already described attention problems
Tics Antipsychotics, (α2 sympath-
omimetics, SSRIs) as “almost regularly occurring in children of this type”
Depression SSRIs, SNRIs, (+ antipsychotics) [13]. Ronald et al. [265] found significant correlations
Bipolar disorder Antipsychotics, (lithium)
between ASD and ADHD pheno and genotypes in
their twins’ early development study, and a probabil-
Anxiety & OCD SSRIs (higher dosage needed),
pregabaline ity of 41% for co-occurrence ADHD in ASD patients.
Seizures Valproic acid, levetiracetam, Nijmijer et al. [225] found genetic linkages between
lamotrigine (and others) ASD and ADHD on chromosomes 7, 12, 15, 16, and
Psychosis Antipsychotics 18. The “dual disorder” is characterized by increased
GI problems Diet? probiotics? psychopathology and psychosocial stress, more com-
promised cognitive and daily functions, including
maladaptive behaviors, and poorer effects of therapy
pends on the type of convulsions and should always [48, 125, 147, 160, 246, 251]. ASD and ADHD share
be combined with psychosocial support [261]. multiple comorbidities, such as dysexecutive prob-
The most commonly used pharmacotherapeutics lems, increased anxiety, sensory integration, sleep,
are valproic acid, lamotrigine, levetiracetam, and affective and central hearing processing disorders,
ethosuximide [96], cf. Table 6. In select syndromes developmental delay, OCD, and epilepsy [187, 223,
such as Landau–Kleffner syndrome or ESES8, corti- 281]. These comorbid conditions will largely deter-
costeroids, ACTH, or immunoglobulin therapy may mine the clinical picture. Unfortunately, ADHD in
be considered [303]. Additional nonpharmacological autistic patients is generally not appropriately treated
therapeutic options for therapy-resistant epilepsies [160]. This could be due to the fact that ADHD was
include vagus nerve stimulation [184], ketogenic diet, excluded in autism diagnosis in ICD-10, a path that
and neurosurgical interventions [114]. It is not clear has now been changed in DSM-5 and ICD-11.
whether an interictal epileptiform EEG may be a co- Treatment of ADHD in patients with ASD should
factor contributing to neurologic deterioration or follow the same multimodal algorithms as for ADHD
progressing developmental retardation [310]. Phar- alone and should include psychoeducation [87, 219,
macologic treatment should always be considered if 238], parental training [41, 85, 87], school-based
symptoms get worse. measures (such as daily record cards [70, 80, 97],
structured task organization, physical activity [39,
Therapy for Common Problems of ASD and 158, 302]), and medication [31, 285, 296]. ADHD
Comorbid Disorders medication is usually less effective, and SE are more
pronounced in ASD patients, especially in those with
Pharmacotherapy for patients with ASD aims at re- ID [48, 85, 241, 255]. Cognitive training [56] and neu-
ducing inappropriate behavior and the related intrafa- rofeedback [88, 212, 252] are less effective and more
miliar and psychological stress, at improving engage- complex. Occupational therapy [49] is useful as an
ment in therapy, health-related quality of life, perfor- adjunct for improving comorbid sensory integration
mance at school and work, social integration and par- and dysexecutive problems.
ticipation, and at treating comorbid problems such Medication for ASD/ADHD targets modulating
as ADHD or seizures [14, 53, 67, 72, 154, 156, 164, dopamine and epinephrinergic transmitter systems,
180, 210, 220, 245, 274]. Limitations include inconsis- thereby increasing dopamine availability in frontal
tent evidence of efficiency and side effects, especially areas and striatum, and downregulating dopamine
with long-term use [107]. A recent study [53] com- moderators. Usually, two types of medication are
pared the benefits and adverse effects of the phar- distinguished: stimulants (methylphenidate, am-
macological treatment of a number of targeted symp- phetamine, lis-dexamphetamine) and nonstimulants
toms in 505 children with ASD. The authors found (atomoxetine and alpha-2 agonists).
small to medium benefits to adverse effects ratios and Stimulants. Effectiveness and compatibility of
methylphenidate, the most frequently used ADHD
medication, have multiply been proven in patients
8 Electrical status epilepticus during slow-wave sleep. with ASD and ADHD, with and without ID [11, 255,

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Table 4 Selected antipsychotics used in children and adolescents with ASD

Drug t 1/2 a Recommended Dose (mg/kg/d) Spec. remarks Referencesb
Risperidone 22 hc 0.005–0.02d also available as syrup Standard therapye [42, 64, 153, 207, 278]
Aripiprazole 60–80 h 0.05–0.1f Standard therapyg [46, 62, 66, 82, 196, 231]
Olanzapine 30–60 h 0.1 SE: sedation, metabolic [93, 136, 291]
Paliperidone 0.5–2 No advantage over risperidone [98]
Quetiapine 7h 0.5–4 Also acts against GADh [109, 122, 200]
Ziprasidone 6h 0.02–0.4 Cardiac SE (QTc ↑) [69, 195]
Pimozide 55 h 0.02–0.08 FGA, therapy resistant tics [79]
a [110], b as related to ASD, c 9-hydroxyrisperidone, d also available as syrup e FDA approved from age 5 years on, f also available as solution, g FDA approved
from age 6 years on, h GAD – generalized anxiety disorder

Table 5 Selected antidepressants used in children and adolescents with ASD to treat depression, anxiety, and OCD
Drug t 1/2 a Recommended Dose (mg/kg/d) Specific remarks Literatureb
Fluoxetine 1–6 d 0.4–0.8 SE: sleep & eating problems [135, 169, 253]
Paroxetine 12–22 h 0.4 Also effective against anxiety disord. and drug treatment [242]
Sertraline 23–26 h 1 Well tolerated [292]
Agomelatin 2.3 h 0.5–1 MT1 & β2 agonist, no systematic studies in adolescents [224]
Duloxetin 8–17 h 0.4–1.2 SNRI [224]
Pregabalin 6h 3–6–10 GABA analogon, pain killer, anticonvulsant, anxiolytic No studies in ASD patients
a [110], b as related to ASD

282, 298]. In addition to the main ADHD symptoms, prevalence of about 17% [104]. In addition, effects on
executive and nonexecutive memory, reaction time, sleep (longer sleep latency, decreased sleep efficiency,
reaction time variability, response inhibition, social and shorter sleep duration) were observed with stim-
communication, and self-regulation are significantly ulant medication [167].
improved with methylphenidate [51, 149, 298] with Atomoxetine. The norepinephrine reuptake in-
somewhat lower effect sizes (around 0.5) in children hibitor and NMDA receptor antagonist possesses
with ASD and ADHD, compared to normally devel- good effectiveness [123, 124] and (compared to
oping children with ADHD. Because of the short t 1/2 methylphenidate) a considerably longer t 1/2 of
of about 2 hours, stimulants are usually administered 35 hours and 99% plasma albumin binding. Be-
in a slow-release formulation, acting for 10–14 hours, cause of its nearly continuous action, atomoxetine
depending on the preparation. About 70% of the is a recommendable alternative to methylphenidate,
normally developing children and half of the children although with a smaller effect size [5, 236, 244], es-
with ASD and ID respond by improved behavior, es- pecially in children who respond with pronounced
pecially with decreased impulsivity, improved cooper- SE to stimulants or are very difficult to handle in the
ation and attention, and less hyperactivity. Behavioral morning and evening hours, when methylphenidate
improvement is more pronounced in children pre- does not act. It may also be recommended in children
senting with hyperactivity and normal IQ [4]. Careful with comorbid depression, tics, or anxiety disorders
dosage titration is recommended because of the large [3, 5]. Atomoxetine needs a longer dosing period (up
variability of efficacy that may be explained geneti- to 12 weeks) and may cause initial fatigue, headache,
cally [206]. The effect of methylphenidate on growth and gastrointestinal SE, wherefore the medication
has been divergently debated with height deficits should initially be started in the evening hours. About
ranging from 0 to 4.7 cm with consistent use [258]. In 15% of the patients may react with increased aggres-
children with severe side effects or decreased respon- sion, requiring discontinuation of atomoxetine and
siveness to methylphenidate, amphetamine [284], either addition of risperidone [207] or aripiprazole
or lisdexamphetamine [52, 54, 127, 145], an inac- [231] or switching to extended-release guanfacine
tive amphetamine precursor that is activated in the [269, 270] or lisdexamphetamine [52].
erythrocytes may be recommended because of their Comparing atomoxetine and amphetamine deri-
larger effect sizes. Amphetamines, and especially vates, higher effect sizes of methyplhenidate slow re-
lisdexamphetamine, also improve mood while acting. lease preparations have been reported [121]. Small
Emotional dysregulation (irritability) is a common but significant cardiovascular effects have been re-
problem in children with ADHD and with ASD, with ported for stimulant and atomoxetine medication
rates around 78% for both disorders [179]. Stimulants [132], mainly small increases of the heart rate and
and atomoxetine act effectively but may also increase of systolic or diastolic blood pressure [132]. Because
emotional dysregulation, although at a much lower significant cardiovascular effects may not be excluded

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Table 6 Anticonvulsants selected

Drug t 1/2 (h)a Recommended Dose (mg/kg/d) Comments Referencesb
Ethosuximide 53 10–20–40 Absences, well tolerated [95]e
No effect on behavior, additive to VPS
Valproic acid 12–16 10–15–30 Enhances GABA-ergic inhibition [96, 136]
Cortical hyperconnectivity, increases risk
Of ASD and malformation when
Administered during pregnancy
Lamotrigine 25–50 0.5–4 Against gen. and PE, well tolerated [23]
Against BSD, no effect on behavior
Levetiracetam 7 20–40–60 Against generalized and PE, SE tiredness [96]
No effect on behavior
Clobazam 18 0.2–0.8 Add-on against prim. generalized and PE [83]
Clonazepam 18–50 0.01–0.4 Against myoclonus epilepsy, SE: dizziness, ataxia [83]
Gabapentin 10–40 Add-on against PE and sec. generalized
Epilepsy, SE tiredness, DRESSc [115]
Sultiame 24 5–6 SE: ataxia, paresthesia, anorexia
Topiramate 19–25 1–4/2 Against PE and generalized epilepsy,
LGSd , SE tiredness
Weight loss, cognitive [68, 133]
impairment
Vigabatrin 5–8 20–60/2
a [110], b as related to ASD, c DRESS = drug rash with eosinophilia and systemic symptoms, d LGS = Lennox–Gastaut syndrome

in a small subgroup of patients (e.g., with slow drug tipsychotics to reduce initially present internal drive
metabolism), occasional blood pressure checks are and suicidality. Psychotherapy adds to antidepressant
recommended. therapy for light to medium severe depression in the
Alpha-2-agonists. Clonidine and extended-release short term but better in the long term. For severe de-
guanfacine are less effective medications against pression, combining psycho and pharmacotherapy is
ADHD core symptoms with some antitic potential, recommended in normotypic children [40, 65].
pronounced tiredness, and gastrointestinal SE, which Suicidality has been reported in 21.3% (7–47%) of
may lead to discontinuing the medication. Hyperac- patients with ASD [142, 324]. Suicidal ideation is very
tivity and impulsivity are improved in about 45% of common in adolescents with ASD, especially in As-
cases [144, 199, 241, 270, 294]. perger’s autists, and is largely related to their increased
Other treatments for ADHD. Mindfulness-based [1, vulnerability to stress, anxiety, and depression, their
259, 268] and neurofeedback therapies [138] have inflexibility, and their proneness to become bullied or
been tried with some success in children with ASD sexually abused [142].
and ADHD. Bipolar disorders are detected in 6–21% of adult
ASD patients [307], and 30% of bipolar I patients meet
Affective Disorders the criteria for ASD [161]. Data for children and ado-
Due to the fact that antidepressant medication is of lescents are still lacking. Therapeutic options include
questionable effect in children and adolescents with SGA, valproic acid, AD medication if severe depressive
ASD, their use may generally not be recommended. symptoms are present, and lithium. Lithium medica-
There is no clear-cut evidence that this recommen- tion also improves social functioning in animals and
dation is also valid for patients with severe depres- adults [190]. Its use may be especially limited in chil-
sion, and the widespread use of antidepressant med- dren because of the narrow therapeutic range, its ef-
ication reflects this challenge, especially in the light fect on thyroid function, the resulting need of a highly
that the prevalence of comorbid depression in autis- compliant and supportive environment, and the con-
tic patients is fourfold compared to the nonautistic siderable and poorly tolerated emotional indifference
population [318]. Combining antidepressants with created by the drug [208, 277].
(low-dose) antipsychotic medication may generally be
recommended for augmenting antidepressant effects Anxiety Disorders
in therapy resistant depressive patients and–although About 40% of children with ASD present with various
with low evidence [78]–in suicidal patients. This re- anxiety disorders, phobias including social phobia,
lates to the long period needed for antidepressant general, and separation anxiety disorder, and OCD
drug effects to become evident and to the effect of an- [323]. They also often react with symptoms of anxiety

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or even panic in reaction to changes in their environ- For contraindications (tricyclics, mirtazapine), see
ment. An early study [292] reported beneficial effects Sect. 3.2.
with low-dose AD medication against anxieties. Stach- Benzodiazepines, especially those targeting GABAA
nik et al [290] reviewed the beneficial effect of neu- receptor subtypes, may attenuate ASD symptoms
roleptics for anxiety disorders in children with ASD. [216]. The clinical significance of this effect is not
High doses of antidepressants may reduce OCD symp- known at present12.
toms in normotypic children. Unfortunately, their ef-
fectiveness is not confirmed in children with ASD [169, Convulsions and Epilepsy
222, 253], possibly because of the background similar- Epilepsy (more than one convulsion) occurs in about
ities of ASD and OCD [271]. 5–46% of children with ASD, (compared to 1–2% in
In general, the treatment methods of choice for children not on the spectrum), depending on the
fears and OCD are parent training, play therapy, and clinical sample and the severity of ID [287]. Comor-
cognitive behavioral therapy (CBT) [6, 60]. Antide- bid epilepsy adds to the impact of ASD on quality
pressants in higher dosages may be tried in individual of life [303] because of a number of additional prob-
patients as an adjunct to cognitive therapies. Because lems, such as cognitive, speech developmental, sleep,
of the poor flexibility of patients with ASD, CBT may affective, medical, social, and behavioral issues [90,
be very laborious in autistic children and adolescents. 118]. Phenotypes and causes are still insufficiently
researched.
Medication Against Sleep Disorders Mitochondrial respiratory chain defects have been
Medication may be helpful in inducing and improv- detected as an important link between epilepsy and
ing disturbed sleep but should be provided with cau- ASD [315]. In addition, three ASD associated syn-
tion: melatonin will improve sleep rhythm in 85% dromes with known genetic cause, tuberous sclerosis,
of the children with ASD even in those without dis- Rett’s syndrome, and fragile X syndrome, are asso-
turbed melatonin circadian rhythm at a daily dosage ciated with epilepsy. Another group of disorders,
of 1–6 mg given 30 minutes before bedtime [108, 267]. epileptic encephalopathies, have been described
Advancing sleep onset will require a smaller dose of in the context of brain dysfunction and increas-
0.2–0.5 mg given 3–5 h prior to the desired sleep time ing autistic symptomatology [74], affecting about
[32, 175]9. 40% of children with convulsions in early childhood.
Other sleep stimulating agents, like valerian, pas- These include early myoclonic encephalopathies,
sion flower, and hops provide placebo support; ben- West, Dravet, Lennox Gastaud, and Landau–Kleffner
zodiazepines, zolpidem, and zaleplon act on GABA syndromes, myoclonus epilepsy in nonprogressive
receptors, helping in inducing sleep but usually have encephalopathies, and continuous spike waves in
a long t 1/2, decrease REM sleep phases, but lead slow-wave sleep (CSWS) [303]. Risk factors include
to habituation, to losing sleep induction effects dur- epilepsies with known structural defects, bilateral
ing prolonged use, and to promoting anxiety [234]. frontal EEG changes, and persistent hypsarrhythmia
Sleep-inducing antidepressants like trazodone are [303].
commonly used. For contraindications (tricyclics,
mirtazapine), see Sect. 3.2. Gastrointestinal Issues
Restless legs syndrome [59, 280]10, another syn- Gastrointestinal distress related to constitutional, be-
drome disturbing sleep and quality of life based havioral, and inflammatory causes is frequently ob-
on a genetic predisposition, dysregulation of iron served in children with ASD and may be related to
metabolism, and the dopaminergic system, suggest altered ASD severity [140]. Alterations of the intesti-
considering iron deficiency as a cause of sleep distur- nal microbiota, permeability, and functioning may,
bance [308]. for example, alter intestinal serotonin metabolism
Other sleep-stimulating agents, like valerian, pas- and cause hyperserotoninemia, alter immune re-
sion flower, and hops, provide placebo support; ben- sponses, and even brain functioning and behavior
zodiazepines, zolpidem, and zaleplon act on GABA via the gut–brain axis [12, 193]. Attempts to influ-
receptors, helping in inducing sleep but usually have ence these disturbances by diets (such as a gluten-
a long t 1/2, decrease REM sleep phases, lead to habit- free diet), probiotics, antibiotic or other “treatments”
uation, may lose sleep induction effects and promote such as detoxification, would need careful prospec-
anxiety during prolonged use [234]. Sleep-inducing tive randomized clinical trials, precise diagnostics,
antidepressants like trazodone11 are commonly used. and well-established clinical algorithms. At present,
this clinical evidence is not available [240]

9 These two references do not primarily refer to children with

ASD.
10 General description.
12 Alterations of the excitatory/inhibitory CNS imbalance in chil-
11 Trittico®. dren with ASD? [99].

120 Practitioner’s review: medication for children and adolescents with autism spectrum disorder (ASD) and. . . K
 review

Irritability, Aggression, Disruptive, and Self-Injuring havior, light therapy14 [84], avoiding daytime sleep-
Behavior ing, etc., and sensory integration therapy [325] have
Impulsive aggression and related disruptive behav- proven to be helpful, although with little evidence
ior, as well as self-injuring behavior are frequently [30].
observed in ASD/ADHD and are the leading cause
for school suspension, clinical referrals, and ward ad- Chronic Tic Disorders, Tourette Syndrome, and
missions [182]. Positive parenting [71], early inten- Stereotypies
sive psychosocial and behavioral interventions [60, Chronic tic disorders and motor stereotypies are com-
76], specific multisystemic programs, such as multi- mon comorbid movement disorders in children and
systemic therapy [131] or the Fast Track program [25, adolescents with ASD [249]. The prevalence of chronic
55], and psychosocial interventions such as T-MAY tic disorder is about 6.5% [281], about 10 times higher
[279] or TRAAY [276], and group sessions for social than in normally developing children. It is character-
competence [101] lead to significant improvements ized by involuntary movements or utterings that vary
of adaptive behavior. Recommendations for medical in onset and frequency, depending on daytime and
treatment include stimulants (in the case of comor- seasonal variations and stress exposure. Treatment is
bid ADHD) and nonstimulant medication, SGAs (cf. necessary if severity and frequency exceed subjective
Sect. 3.1), antidepressant and mood stabilizing agents or environmental tolerance. Effective treatment op-
[48, 68, 75, 91, 116, 159]. In addition to pharmacother- tions [249] (besides relaxation, stress reduction, and
apy, behavioral and social competence training, and bio or neurofeedback) include antipsychotics such as
parental counselling are strongly recommended. risperidone, aripiprazole, or pimozide, eventually with
added pentoxyfylline, and the anticonvulsant topira-
Sleep Disorders mate are effective, whereas haloperidole, levetirac-
Independently of their intellectual capacity, up to etam, guanfacine, and atomoxetine, as well as meto-
2/3 of children with ASD suffer from sleep problems: clopramide and odansetron, have not proven effective
delayed sleep onset, frequent night awakenings, re- [249, 262].
duced total sleep time, dys and parasomnias [26, 57,
63, 157, 175, 189, 197, 205, 256, 308, 317]. These prob- Other Substances, Supplementary and Alternative
lems often persist into adulthood. The causes range Therapies
from poor sleep hygiene and inconsistent parental
behavior [317], (self) regulatory problems and cen- Among the “newer” pharmacologic concepts (such
tral excitatory/inhibitory imbalance, delayed sleep as IGF-1, memantine, D-cycloserine, arbaclofen,
pattern maturation, a disturbed hypothalamic-pitu- and oxytocin [240, 300]), only three show promise
itary-adrenal axis, and decreased and dysrhythmic for the future: oxytocin with the objective to im-
melatonin secretion to decreased binding of mela- prove sociogenic behavior, beta blockers to reduce
tonin to its transporter protein and melatonin recep- stress, and the glutamate antagonist, 2-methyl-6-
tor dysfunction [57, 141, 202]. Recently, slow-release (phenylethynyl)pyridine (MPEP), to reduce stereo-
melatonin13 was approved by the European Medicines typic behavior [94]. For the latter substance, it is
Agency for the treatment of sleep disorders in children feared that sociogenic behavior may deteriorate dur-
with ASD from the age of 2. In addition, anxiety [305], ing treatment [297].
ADHD/ASD associated sleep and sensory integration In the short term, intranasal oxytocin enhances
problems [126] leading to increased external stimu- motivation and attention to social stimuli, improves
lation (or decreased stimulus filtering), and cerebral social initiative, understanding, learning [8, 22, 176],
convulsions may disturb sleep and quality of life of and better recognition of emotions [111]. Unfortu-
affected children and, consequently, of the whole nately, these improvements were not substantiated
family. Therefore, sleep diagnostics and treatment in long-term trials [7, 112, 313, 321, 322]. A meta-
are important for both children with ASD and their analysis [248] reported medium-effect sizes for pro-
families [174, 308]. longed oxytocin therapy in small samples. Reasons
Restless legs syndrome [59, 280], another syndrome for the variation in oxytocin response include time
disturbing sleep and quality of life based on a genetic dependency of the oxytocin response [230], single
predisposition, dysregulation of iron metabolism, and nucleotide polymorphisms of the oxytocin receptor
the dopaminergic system, suggest considering iron [148], and lasting effects of postnatal stimulation of
deficiency as a cause of sleep disturbance [308]. the oxytocin system [300]. When studying oxytocin
Behavioral measures [30, 283, 314] like fixed bed- effects patients and targets must be carefully selected.
time routine, providing sleeping cues and a low stim- Therefore, the clinical usefulness of oxytocin is still
ulation evening routine, supporting self-soothing be- a matter of debate [228, 306]. Melanocortin, stimu-
lating oxytocin release, could be a useful alternative

1410.000 lux for 1/2 h in the early evening and/or morning in or-
13 Slenyto®. der to synchronize the circadian rhythm better.

K Practitioner’s review: medication for children and adolescents with autism spectrum disorder (ASD) and. . . 121
 review

[215], but large clinical trials are lacking. Still, a special herbal remedies, secretin), and mind–body inter-
edition of “Brain Research”15 provides a comprehen- ventions (such as prayer, shamanism, biofeedback,
sive overview about the state of research. meditation, and relaxation) are more often perceived
There is only limited evidence for using beta block- efficacious than body-based methods (such as sen-
ers for reducing stress-related autoaggressive behav- sory integration therapy [325], massage, craniosacral
ior [312] or memantine for improving language and therapy, neurofeedback, and special exercises) or en-
memory functions [233]. Defects of GABA-A recep- ergy therapies (healing touch, energy transfer) [120].
tors, leading to deficient synaptogenesis, have been Technology based interventions seem promising be-
demonstrated in fragile X syndrome, a pervasive de- cause of the attention sustaining potential, but, at
velopmental disorder with known genetic defect16. present, evidence of the success of such approaches
Ganaxolone, a strong GABA-A agonist, was used in is poor [172, 250]. Examples are interventions for
a controlled clinical study [29, 188] and was found to acquiring language skills [226], for differentiating fa-
be safe but only effective in a subgroup of patients cial expressions [19], treating food selectivity [20], or
with fragile X syndrome, high levels of anxiety, and anxiety or stress management [37].
low intellectual capacity. A number of physicians encourage multivitamins
Medical cannabis, especially for ADHD, tics, sleep (49%), essential fatty acids (25%), melatonin (25%),
problems, behavioral problems, and anxiety [2, 134, and probiotics (19%), and discourage withholding
247], may improve symptoms but does not lead to (76%) or delaying immunizations (55%), chelation
remission. Treatment evidence at present is limited (61%), anti-infectives (57%), or secretin (43%) [120].
to anecdotical reports and a few small studies; three It has to be stated that there is no clinical evidence
further studies are to be expected. Treatment op- for applying specific (e.g., gluten-free or pro-biotic)
tions should, therefore, be restricted to single patients diets [203], vitamins18 [155, 237], oligominerals, herbal
in whom standard treatment did not improve severe medicine [311], transfer of energy, chelates19 [151], or
symptoms. biologicals such as secretin [180, 186]. It has been
Various behavioral and functional therapies, such found that 10% of parents even use potentially dan-
as structured behavioral therapies [178, 254, 299], gerous “medication” such as “whole-brain extracts”
communication and social skills training [177, 213], [185]. Medication from the Far East, such as tradi-
occupational therapy [49, 194], mindfulness [259], tional Chinese medicine or acupuncture, or osteopa-
play teaching [162], music [217, 289], and speech thy may be useful in the short-term run in improving
therapy, have been shown to have beneficial effects single symptoms (restlessness, sleep disturbance); the
in improving development, behavior, speech, social long-term outcome is rather dubious [45].
functioning, and quality of life [146, 191, 192, 220,
221, 275]. Physical exercise is an effective treatment Discussion
option, especially in children with dual disorder, ASD
and ADHD [128, 286, 302]. Pharmacotherapy in children and adolescents with
Alternative, “natural” treatments seem less inva- ASD may be helpful in overcoming otherwise not re-
sive, safer (there are no reports on dangerous action), solvable behavioral and attentional problems (see Ta-
more intuitive to understand, and easier to procure. ble 2 for an overview of indications and classes of
Parents are concerned with the safety or side effects useful substances). Individualized treatment is al-
(listed in the package leaflet) of medication or are dis- ways mandatory, Reviewing the extensive literature on
appointed because conventional medication did not pharmacotherapy of ASD, a few trends may be recog-
change the core symptoms of ASD [120]. Therefore, nized:
alternative therapies are very popular [186, 191, 316]; 1. Conventional therapy, although mostly funded on
a third of the parents of children with ASD have tried extensive controlled studies, has its limits, espe-
“alternative”, “integrative”, or “complementary”17 ther- cially when treating irritability and temper tantrums.
apies [185, 186, 191]. A higher educational level of These problems should be restricted by early behav-
the mothers predicted the use of alternative therapies ioral treatment. Unfortunately, these treatments are
[120]. Half of the families use alternative therapies, tedious and not available everywhere. In addition,
although they do not rate them as useful. the question of the impact of comorbid conditions
Most of these therapies are used as an adjunct has not been solved as yet.
to conventional therapy. Biologically based thera- 2. Pharmacologic treatments are not sufficient; the
pies (such as diet[239, 293], vitamins and minerals, primary ASD treatment, especially for children with
food supplements such as omega-3 fatty acids [150], intellectual disabilities, will remain structured and

15 Vol. 1580:1–232(2015).
16 Fragile X mental retardation 1 (FMR1) gene on chromosome X 18 This is disputed for vitamin D: evidence [155] vs. no evidence

(Xa27.3). [204].
17 Alternative and conventional medication. 19 For heavy metal detoxication.

122 Practitioner’s review: medication for children and adolescents with autism spectrum disorder (ASD) and. . . K
 review

functional therapy, as well as parental empower- side effects, and, and in adolescents, to teratogenic
ment and support. side effects for the offspring.
3. Therapies aiming at improving the core symptoms The rediscovery of the gut–brain axis is a relatively
of ASD, such as social communication: novel thera- new field of research and might, therefore, be overesti-
pies, e.g., oxytocin, are encumbered with the com- mated by parents. More prospective studies will shed
plex functioning of our social brain, which is out- light on the effects of dietary and probiotic measures.
lined in the first days of life or even before. Alternative treatments are comprehensively largely
4. At present, genetically based therapies are not vis- overestimated for their effects, ranging from dietary
ible on the horizon, mostly because the genetic to physical and possibly endangering measures. Be-
background of ASD is so complex that it will prob- cause alternative “medications” are not controlled
ably need further years of intensive research to link for their action in prospective randomized trials, it is
clinical pictures to genetic variants and establish difficult to argue against the use of such substances
repair options. in the general public, mostly because “natural” sub-
stances are considered harmless and innocuous (see
Behavioral problems, including irritability, reactive Sect. 3.4).
and proactive aggression, disruptive and self-stimu- In summary, we compiled an overview on sub-
lating behavior, restlessness, and temper tantrums, stances that may be advantageously used in children
are among the most important therapeutic targets with ASD with the aim of improving social behavior,
in children with ASD. Because of their very limited learning ability, and quality of life of the children and
flexibility [102] and working memory problems [117], their environment. The approach is rather defensive,
children with ASD easily become despaired and help- mostly targeting undesired symptoms. Future work
less and express this in externalizing behavior that and experience should focus on desired changes of
can become difficult to control. Pharmacologic treat- core symptoms, on long-term efficacy, on reducing
ment, mostly using antipsychotics, must find a com- polypragmasia and undesired drug effects, and on
promise between behavioral control, oversedation, avoiding overtreatment, especially if behavioral ther-
and (mostly metabolic) side effects. apies are available as an alternative. On the other
Depressed mood and anxiety disorders call for psy- hand, the benefits of carefully prescribed medication
chotherapy and, in selected patients, for treatment should always be recognized.
with antidepressants. The problems with antidepres-
Funding Open access funding provided by Medical University
sant medication are its reduced efficacy in autistic of Vienna.
vs. normally developing children (see Sect. 3.2), and,
again, walking the tightrope between brightening Conflict of Interest The authors state that no author has
mood or reducing anxiety or obsessions and compul- a conflict of interest to declare.
sions and an increased behavioral activation. Open Access This article is licensed under a Creative Com-
Sleep problems are observed in a majority of pa- mons Attribution 4.0 International License, which permits
tients with ASD. Sleep hygiene and bedtime routines use, sharing, adaptation, distribution and reproduction in
should be tried before trying medication, and sleep- any medium or format, as long as you give appropriate credit
related side effects of stimulant therapy should also to the original author(s) and the source, provide a link to
the Creative Commons licence, and indicate if changes were
be considered as a promoting factor of sleep dysfunc- made. The images or other third party material in this article
tion. Melatonin is the first-line drug, especially for dif- are included in the article’s Creative Commons licence, unless
ficulties in falling asleep. It is effective in about two- indicated otherwise in a credit line to the material. If material
thirds and counterbalances inherited melatonin dys- is not included in the article’s Creative Commons licence and
function. It should be noted that falling asleep with your intended use is not permitted by statutory regulation or
lights on (especially from computer or mobile phone exceeds the permitted use, you will need to obtain permis-
sion directly from the copyright holder. To view a copy of this
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tion.
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