Handbook of Clinical Neurology, Vol.

165 (3rd series)

Psychopharmacology of Neurologic Disease
V.I. Reus and D. Lindqvist, Editors
https://doi.org/10.1016/B978-0-444-64012-3.00024-1
Copyright © 2019 Elsevier B.V. All rights reserved

Chapter 24

The psychopharmacology of autism spectrum disorder

and Rett syndrome

ANTONIO M. PERSICO*, ARIANNA RICCIARDELLO, AND FRANCESCA CUCINOTTA

Interdepartmental Program “Autism 0-90”, "Gaetano Martino" University Hospital, Messina, Italy

Abstract
Autism spectrum disorder (ASD) appears in early childhood and is characterized by persistent deficits in
communication and social interaction, as well as restricted interests, repetitive behaviors, and unusual sen-
sory issues. ASD can be idiopathic or syndromic, in the latter case representing one of the many manifes-
tations of a genetic disorder, such as Rett syndrome. Psychopharmacology cannot directly ameliorate core
autistic symptoms, but rather aims at treating comorbid disorders, such as ADHD, sleep disturbances, psy-
chomotor agitation and aggressiveness, seizures, and anxiety. Until the 1990s, it was mainly based on typ-
ical neuroleptics and tricyclic antidepressants, whereas second-generation antipsychotics later became
first-line drugs for these same indications. In general, selective serotonin reuptake inhibitors have not
proven effective in ASD patients. Psychostimulants are frequently prescribed, but display modest efficacy
and enhanced potential for side effects and noncompliance. Targeted patients benefit from mood stabilizers
and antiepileptic drugs. Experimental drug treatments for ASD include oxytocin and vasopressin, bume-
tanide, sulforaphane, nutritional supplements, memantine, and D-cycloserine. Work performed on syndro-
mic forms, represents an important source of information for experimental therapies of ASD and
knowledge of the unique mechanisms underlying autism in each individual patient may in the future
pave the path to personalized drug treatments.

corresponding to 1/59 children aged 8 in 2014 (Baio

INTRODUCTION
Autism spectrum disorder (ASD) is a developmental dis-
order that appears in early childhood and is characterized
by (A) persistent deficits in communication and social
interaction as well as (B) restricted interests, repetitive
behaviors, and unusual sensory issues (APA, 2013).
These core symptoms are frequently associated with
emotional and behavioral disturbances, including anxi-
ety, irritability, labile mood, inattention, hyperactivity,
and sleep problems, which may lead to functional impair-
ment and significant emotional and economic burden for
caregivers (Simonoff et al., 2008).
The prevalence of ASD in the second half of the 1980s
stood at 2–5/10,000 children, posing autism as a rare dis-
ease (Fombonne, 2005). Thirty years later, in the United
States the prevalence has risen to 168/10,000 children,
et al., 2018). The M:F ratio is between 3:1 and 4:1
(Loomes et al., 2017). Female sex is associated with a
higher disease threshold, probably due to genetic,
epigenetic, and hormonal protection (Werling, 2016).
Approximately 90% of ASD cases are “idiopathic,”
whereas 10% are “syndromic,” i.e., ASD is part of a
broader genetic syndrome (Persico and Napolioni,
2013). From a biologic and, to some extent, clinical
standpoint, Rett syndrome represents one of the best-
studied examples of syndromic autism (Rett, 1966;
Amir et al., 1999).
At present, evidence-based therapeutic interventions
in ASD include a variety of approaches, such as behavior
therapy, speech therapy, occupational and physical
therapy, social skills training, special education, and
vocational training, among other nonpharmacologic

*Correspondence to: Antonio M. Persico, Interdepartmental Program “Autism 0-90”, “Gaetano Martino” University Hospital, via
Consolare Valeria 1, I-98125 Messina, Italy. Tel: +39-090-221-3143, Fax: +39-090-293-0414, E-mail: apersico@unime.it
392 A.M. PERSICO ET AL.
interventions (Tonge et al., 2014; Wong et al., 2015). As
yet, pharmacologic treatment is not directed to the core
symptoms of ASD, but rather to comorbid disorders
and problem behaviors, such as irritability, anxiety,
aggression, self-injurious behavior, ADHD, sleep disor-
ders, and seizures. Until the end of the 1980s, typical neu-
roleptics and tricyclic antidepressants (TCAs) were the
only two viable options to reduce behavioral symptoms
in ASD. Currently, the array of drugs that have proven
their efficacy on disorders and symptoms comorbid with
ASD has significantly risen, although the vast majority
must be prescribed “off-label” (Persico et al., 2015).
For most medications, limited data are available regard-
ing efficacy in autistic individuals, especially children
and adolescents, owing to small sample sizes, diagnostic
heterogeneity, and methodological difficulties in orga-
nizing multicenter trials (Persico et al., 2015).
This chapter provides an overview of psychopharma-
cologic agents either approved or currently in use for
ASD and Rett syndrome. We then summarize innovative
pharmacologic agents undergoing clinical trials, aimed at
translating our ever-increasing knowledge of the patho-
physiology of these disorders into pharmacologic tools
able to ameliorate the core symptoms of ASD.
TYPICAL NEUROLEPTICS AND
TRICYCLIC ANTIDEPRESSANTS
Neuroleptics have been the most widely studied class of
psychopharmacologic agents in autism over the past
35 years. Starting in the 1960s, children and adolescents
with autism were enrolled in randomized controlled
trials (RCTs) of first-generation antipsychotics, espe-
cially haloperidol, thioridazine, and trifluoperizine.
These agents were found to decrease hyperactivity,
stereotypic behaviors, social withdrawal, aggressive-
ness, and temper outbursts. For example, the first
RCT, enrolling 45 children aged 2–7 years with DSM-
III autistic disorder, showed significant positive effects
of haloperidol (0.25–4.0 mg/day) on global functioning
and multiple behavioral problems, as measured with
Children’s Psychiatric Rating Scale (CPRS) and Clinical
Global Impression (CGI) scores, but no improvement in
learning abilities was recorded (Anderson et al., 1989).
The major limitation of these drugs is their side-effect
profile, ranging from relatively benign dry mouth and
sedation to severe parkinsonism, acute dystonia, tardive
dyskinesia, and neuroleptic malignant syndrome. Des-
pite these adverse effects, haloperidol and other neuro-
leptics remained the most prescribed drugs in ASD
until the 1990s.
TCAs block several monoamine transporters, pri-
marily the serotonin (5-HT) and norepinephrine (NE)
transporters SERT and NET, respectively. Through this
mechanism, they enhance extracellular monoamine
levels by reducing their uptake. TCAs, such as desipra-
mine, imipramine, nortriptyline, amitriptyline as well
as buproprion, a dopamine reuptake blocker, have been
used to treat individuals with autism for comorbid anxi-
ety, obsessive–compulsive disorder (OCD), major
depression, and attention deficit hyperactivity disorder
(ADHD), but clinical response and side effect severity
appear less favorable compared to the nonautistic popu-
lation and warrant caution. Antagonizing multiple cho-
linergic, histaminergic, and adrenergic receptors, in
addition to monoamine transporters, TCAs frequently
produce side effects, including dry mouth, constipation,
urinary retention, blurred vision, sinus tachycardia,
impaired cognition, sedation, impaired motor coordina-
tion, weight gain, balance problems, orthostatic hypoten-
sion, cardiac toxicity, central nervous system (CNS)
depression, and seizures. Nonetheless, despite producing
more frequent and severe adverse effects than, for exam-
ple, fluoxetine or fluvoxamine, in healthy patients with-
out seizures and with normal cardiac function, TCAs are
generally safe and well tolerated.
The predominantly 5-HT reuptake blocker most stud-
ied in ASD is clomipramine. Superior to placebo and to
desipramine (a predominantly NE reuptake blocker), clo-
mipramine was able to improve autistic symptoms,
anger, and repetitive behaviors in 57% of ASD subjects
enrolled in a double-blind RCT (Gordon et al., 1993).
However, progressively increasing doses of clomipra-
mine, up to a maximum of 250 or 5.0 mg/kg/day for
5 weeks, showed no therapeutic advantage and resulted
in severe side effects in an open trial on eight ASD chil-
dren aged 3.5–8.7 years (Sanchez et al., 1996). An RCT,
comparing the efficacy of clomipramine, haloperidol,
and placebo in 31 subjects with ASD, found no signifi-
cant difference between clomipramine and placebo on
stereotypy, irritability, and hyperactivity recorded using
the Aberrant Behavior Checklist (ABC) (Remington
et al., 2001). Moreover, many participants receiving clo-
mipramine discontinued treatment due to side effects or
lack of efficacy. Nortriptyline, a predominantly NE reup-
take blocker, may reduce hyperactivity, aggressiveness,
and ritualized behavior (Kurtis et al., 1966), and be better
tolerated than imipramine (Campbell et al., 1971).
Tianeptine, pharmacologically distinct from TCAs but
sharing at least some properties with this drug class,
was able to reduce abnormal behaviors, such as inade-
quate eye contact and speech abnormalities, significantly
more than placebo when rated by parents and teachers,
but clinician ratings did not show any significant dif-
ference between tianeptine and placebo (Niederhofer
et al., 2003). Adverse effects, including drowsiness
and reduced activity levels, were recorded in a sizable
number of patients treated with tianeptine.
 PSYCHOPHARMACOLOGY OF ASD AND RETT SYNDROME
ATYPICAL ANTIPSYCHOTICS
Second-generation antipsychotics (SGAs), also known
as “atypical antipsychotics” emerged in the 1980s. This
new group of neuroleptics shares some effects with first-
generation neuroleptics, but differs in neurochemical
profile, effectiveness, and side effects. A shift toward
the use of SGAs was largely driven by their lower risk
of extrapyramidal side effects, although they can pro-
mote a metabolic syndrome, characterized by weight
gain, elevated lipid and prolactin serum levels, and pos-
sibly type 2 diabetes mellitus. In general, they have a dif-
ferent receptor blocking profile, being less effective on
dopamine D2 as compared to D1 receptors and also
blocking many 5-HT receptor subtypes. Atypical anti-
psychotics include risperidone, paliperidone, aripipra-
zole, olanzapine, clozapine, quetiapine, ziprasidone,
asenapine, sertindole, and zotepine. The FDA approved
risperidone in 2006 and aripirazole in 2009 for the treat-
ment of irritability in ASD, including tantrums, aggres-
sion, and self-injury, whereas the European Medicine
Agency has only approved risperidone.
Risperidone, a potent antagonist at dopamine D2 and
serotonin 5-HT2A receptors, has been one of the most
extensively studied medications in ASD. Several open
studies have supported the efficacy, safety, and tolerabil-
ity of risperidone in the treatment of autistic behaviors,
irritability, aggression, and hyperactivity (Findling
et al., 1997; McDougle et al., 1997; Nicolson et al.,
1998; Masi et al., 2001; Nishimura et al., 2003;
Gagliano et al., 2004; Kent et al., 2013a,b; Lamberti
et al., 2016). Multiple RCTs have also produced defini-
tive evidence of efficacy on irritability and suggestive
evidence for repetitive behaviors. Long-term efficacy
of risperidone was reported in the 2005 RUPPAN study,
in which an initial open-label 4-month treatment period
at an established effective dose was followed by an
8-week double-blind, placebo-controlled withdrawal
period; over 60% of youth relapsed while on placebo
as compared to 12.5% on risperidone (RUPPAN,
2005a). However, symptom improvement with risperi-
done came at the expense of weight gain, which averaged
5.1 kg (RUPPAN, 2005a). Several double-blind RCTs
found risperidone effective in treating motor stereoty-
pies, hyperactivity, impulsivity, agitation, and aggression
in monotherapy (McDougle et al., 1998; McCracken
et al., 2002; Malone et al., 2002; Shea et al., 2004;
Troost et al., 2005; McDougle et al., 2005; Luby et al.,
2006; Nagaraj et al., 2006; Pandina et al., 2007; Aman
et al., 2008; Kent et al., 2013a; Ghanizadeh et al.,
2014; Aman et al., 2015). Interestingly, in a double-blind
RCT of 96 children, 5–17 years old, higher doses of ris-
peridone (1.75 mg/day for >45 kg) contributed to greater
change in the ABC-I as compared to lower doses
393
(0.175 mg/day for >45 kg) (Kent et al., 2013a). The side
effect profile of risperidone in individuals with autism is
generally favorable. Neurologic side effects are rela-
tively unusual, although acute extrapyramidal symptoms
still occur. The most common side effect of risperidone in
autistic patients is also a metabolic syndrome, with
increased appetite, weight gain, and, less frequently,
sedation. Direct comparison of haloperidol and risperi-
done in 30 children with ASD, aged 8–18 years, found
risperidone to be more effective than haloperidol in
the treatment of behavioral symptoms, impulsivity,
language skills, and impaired social relations (Miral
et al., 2008). Finally, risperidone modulates important
astroglial functions, possibly exerting antioxidant and
neuroprotective effects in ASD (Quincozes-Santos
et al., 2009).
Aripiprazole acts as an agonist, partial agonist, or
antagonist at dopamine D2 receptors, depending on cell
type and function examined (Shapiro et al., 2003). It also
acts as an inverse agonist at 5-HT2B receptors, as a partial
agonist at 5-HT1A, 5-HT2A, 5-HT2C, D3, and D4 recep-
tors, as an antagonist at 5-HT7, a1-adrenergic, and
H1-histamine receptors (Shapiro et al., 2003). This pecu-
liar mechanism of action allows aripiprazole to act simul-
taneously as an antagonist in hyperdopaminergic and as
an agonist in hypodopaminergic brain regions or condi-
tions. Several open-label studies have shown the tolera-
bility and safety of aripiprazole therapy, as well as its
effectiveness for the treatment of hyperactivity and irri-
tability in autistic children and adolescents (Stigler
et al., 2009; Marcus et al., 2011; Ishitobi et al., 2013;
Maloney et al., 2014; Lamberti et al., 2016; Ichikawa
et al., 2018). Numerous RCTs have also provided strong
evidence of efficacy in reducing irritability, hyperactiv-
ity, and stereotypic behavior in autistic children and ado-
lescents aged 6–17 years, both acutely and following
long-term treatment (Marcus et al., 2009; Owen et al.,
2009; Aman et al., 2010; Robb et al., 2011; Findling
et al., 2014; Ichikawa et al., 2017). In addition to these
studies, an 8-week open-label trial conducted on 10 pre-
schoolers with ASD, aged 3–6 years, reported a signifi-
cant reduction in irritability, stereotypic behavior, and
hyperactivity (Habibi et al., 2015). Direct comparison
of aripiprazole to risperidone in a 2-month double-blind
RCT showed similar efficacy in treating irritability for
the two drugs, as measured with the ABC-I, but a faster
onset of action for aripiprazole (Ghanizadeh et al., 2014).
The most frequent side effects include increased appetite
and weight gain, sedation, and psychomotor agitation,
but side effects overall occurred less frequently com-
pared to other SGAs, especially serious EKG and cardiac
adverse events (De Hert et al., 2011; Ho et al., 2012).
Children and adolescents tend to have more pronounced
side effects from aripiprazole when antipsychotic-naïve
394 A.M. PERSICO ET AL.
than if previously treated with another SGA, but drug
discontinuation rates are similar (10.8% vs 8.3%,
respectively) (Mankoski et al., 2013).
Olanzapine use in ASD has been assessed only in one
small RCT (Hollander et al., 2006a), three prospective
open-label trials (Potenza et al., 1999; Kemner et al.,
2002; Fido and Al-Saad, 2008), and one open-label com-
parison with haloperidol (Malone et al., 2001). Hollander
et al. (2006a) conducted an 8-week RCT on 11 autistic
children, aged 6–11 years, randomized to receive olanza-
pine (mean dose 10 mg/d) or placebo. Significant
improvements were recorded in the primary outcome
measure (CGI-I), but not in secondary outcome measures
(CY-BOCS and Overt Aggression Scale-Modified).
Common adverse effects included sedation and weight
gain; rhinitis, “glazed eyes,” constipation, and insomnia
were also more frequent in olanzapine-treated children
compared to placebo. In a 6-week open-label study,
5/6 and 3/6 olanzapine- and haloperidol-treated ASD
children, respectively, were rated as “responders” using
the CGI-I (Malone et al., 2001). Collectively, these
results and those from open-trials indicate that olanza-
pine may be beneficial, especially for irritability, to chil-
dren and adolescents who do not respond well to
risperidone or aripiprazole.
Lurasidone is a novel SGA with potent 5-HT2A,
5-HT7, D2, and noradrenergic a1 receptor antagonism,
as well as partial agonism at the 5-HT1A receptor
(Ishibashi et al., 2010). In addition to approved indica-
tions for adult schizophrenia and bipolar disorder, this
pharmacologic profile may also be associated with an
antidepressant effect and lesser side effects involving
weight gain and changes in metabolism. One recent mul-
ticenter double-blind RCT study enrolled 150 ASD
patients, aged 6–17 years, randomized to receive either
lurasidone 20 mg/day (N ¼ 50), 60 mg/day (N ¼ 49), or
placebo (N ¼ 51) for 6 weeks. Lurasidone was not signif-
icantly superior to placebo in ABC Irritability or
CY-BOCS scores at any dose, but produced significantly
greater improvement at 20 mg/day over placebo using the
CGI-I. Common side effects included nausea and drows-
iness, with only minor changes observed in weight and
metabolic parameters (Loebel et al., 2016). A case report
showed improvement in irritability, perseveration, and
aggression in a 13-year-old autistic boy at an initial dose
of 10 mg/day, increased to 30 mg/day, without significant
adverse effects (Millard et al., 2014).
No RCT has been published to this date for clozapine,
quetiapine, ziprasidone, or newer SGAs, including pali-
peridone, iloperidone, and asenapine. However, open tri-
als report effectiveness, and these drugs are often used in
clinical practice. Clozapine has been reported to be effec-
tive in improving hyperactivity and aggression in
treatment-resistant autistic children, adolescents, and
adults who failed to respond to other first-line treatments
(Zuddas et al., 1996; Chen et al., 2001; Lambrey et al.,
2010; Sahoo et al., 2017). It is used as second-line
treatment because of potentially severe or even life-
threatening side effects (especially agranulocytosis,
seizures, sedation, and cardiomyopathy), which require
medical follow-up and regular blood tests for as long
as the patient continues to take the medication. Quetia-
pine has produced contrasting results. Two small
open-label studies found quetiapine not effective and
poorly tolerated in children and adolescents with ASD
(Martin et al., 1999; Findling et al., 2004). However, a
retrospective study of 20 patients (aged 5–28 years)
who received a daily dose of quetiapine between
25 and 600 mg over a period of 4–180 weeks showed
modest improvements in maladaptive behavior, espe-
cially in CGI-S scores (Corson et al., 2004). Another ret-
rospective study suggests that 40%–60% of autistic
patients may benefit from quetiapine treatment
(Hardan et al., 2005). Finally, an open-label trial of
11 adolescents aged 13–17 years found quetiapine well
tolerated and effective in treating aggressive behavior
and sleep disturbances, but less so in autistic behaviors
(Golubchik et al., 2011). Ziprasidone has an interesting
pharmacologic profile, characterized by: (a) strong
5-HT2A receptor antagonism, (b) moderate antagonism
at 5-HT1D, dopamine D2, noradrenergic a1, and hista-
mine H1 receptors, (c) antidepressant and anxiolytic
effects through 5-HT1A receptor antagonism and
norepinephrine reuptake inhibition. Ziprasidone
(20–160 mg/day) can have beneficial effects for ASD
children and adolescents, without producing significant
weight gain, metabolic changes, prolactin increase, or
other severe adverse effect (McDougle et al., 2002;
Goforth and Rao, 2003; Duggal, 2007; Malone et al.,
2007; Dominick et al., 2015). Side effects include QTc
increases and occasional acute dystonic reactions
(Malone et al., 2007). The efficacy of ziprasidone on irri-
tability in youth with ASD may be somewhat lower com-
pared to risperidone and aripiprazole, but it is well
tolerated (Dominick et al., 2015). Paliperidone is the
extended-release major active metabolite of risperidone.
Only two case reports and one 8-week open-label study
suggest that it may be effective on irritability in ASD
children and adolescents, at a mean final dosage of
7.1 mg/day (range 3–12 mg/day) (Stigler et al., 2010,
2012; Kowalski et al., 2011). The drug is generally well
tolerated and side effects appear superimposable to those
of risperidone, most frequently including weight gain
and increased prolactin levels (Stigler et al., 2012).
There are no studies published to date on the use of
some newer SGAs, namely asenapine and iloperidone,
in ASD children and adolescents. These drugs are both
D2 and 5-HT2A receptors antagonists, approved by the
 PSYCHOPHARMACOLOGY OF ASD AND RETT SYNDROME
FDA in 2009 for the treatment of adults affected by
schizophrenia.
In summary, antipsychotics can be very useful for
children and adolescents with autism to treat irritability,
psychomotor agitation, temper outbursts, or aggression
toward self or others. Prominent hyperactivity and
impulsivity may also respond better to neuroleptic treat-
ment than to typical first-line psychostimulants, in low-
functioning autistic individuals or in patients who
develop greater agitation when administered psychosti-
mulants. Once problem behaviors are reduced, behav-
ioral and educational interventions with autistic
children and adolescents often develop greater efficacy.
SGAs are equally or more effective than typical neuro-
leptics and safer in terms of side effect profile. Typical
neuroleptics remain a viable option when ASD patients
are nonresponsive to at least two SGAs, noncompliant
to several SGAs due to important side effects, or when
SGAs, including clozapine, are contraindicated due to
documented medical reasons.
SELECTIVE SEROTONIN REUPTAKE
INHIBITORS
To date, three selective serotonin reuptake inhibitors
(SSRIs) have received regulatory approval in Europe
for use in the pediatric population: fluoxetine for moder-
ate to severe major depressive episodes starting at age 8,
and sertraline and fluvoxamine for OCD after 6 and
8 years of age, respectively (Persico et al., 2015). These
drugs raised initial hopes of clinical usefulness in ASD,
based on their well-known efficacy on obsessive–
compulsive symptoms and on 5-HT blood levels, found
elevated in approximately 25% of autistic individuals
(Gabriele et al., 2014). Contrary to this expectation,
results with SSRIs in ASD have been generally disap-
pointing. Overall, RCTs involving fluoxetine, fluvoxa-
mine, fenfluramine, and citalopram provided modest
and conflicting evidence of efficacy on repetitive behav-
iors and compulsions (Hollander et al., 2005, 2012;
Williams et al., 2013; Mouti et al., 2014), but fluoxetine
has been shown to increase regional blood flow in the
anterior cingulate gyrus and orbitofrontal cortex
(Buchsbaum et al., 2001). The antianxiety effects of flu-
oxetine may also explain the occasional observation of
some improvement in (a) core ASD symptoms, including
an increase in eye contact, social initiation and respon-
siveness, and repertoire of interests; (b) irritability and
problem behaviors, including decreased tantrums and
aggression toward self and others; (c) attention deficit
(initiating, shifting, and sustaining attention), leading
altogether to better social adaptation and inclusion
(Hollander et al., 2012). However, improvement is
often clinically marginal and side effects, especially
395
hyperactivity, impulsivity, and sleep disturbance, are
common in ASD children and adolescents, frequently
leading to noncompliance or to treatment interruption.
Fluvoxamine has been proven effective in treatment
of repetitive, maladaptive, and aggressive behaviors in
some adults, but not in children and adolescents with
ASD, who tend to experience adverse effects very fre-
quently (McDougle et al., 1996, 2000; Sugie et al.,
2005). Also, citalopram is not more effective than pla-
cebo on repetitive behaviors in children and adolescents
with ASD, and is more likely to be associated with
adverse effects, including increased energy level, impul-
siveness, decreased concentration, hyperactivity, stereo-
typy, diarrhea, insomnia, dry skin or itching, and
prolonged seizure (King et al., 2009). There are no RCTs
of paroxetine, sertraline, escitalopram. A case report pro-
vides anecdotal evidence of efficacy in the treatment of
repetitive behaviors, anxiety, and temper tantrums for
paroxetine in a 7-year-old nonresponder to fluoxetine
and fluvoxamine (Posey et al., 1999). One open-trial pro-
vides some evidence of efficacy for paroxetine on self-
injurious behavior in intellectual disability (Davanzo
et al., 1998). A retrospective study of 37 adults with intel-
lectual/neurologic disabilities and autistic traits reported
improvement in only 13 cases and a high incidence
of side effects, including vomiting, psychomotor agita-
tion, drowsiness, hypomanic behavior, aggressiveness,
insomnia, seizures, and skin rushes (Branford et al.,
1998). The effectiveness of sertraline in ASD children
and adults is mainly linked to anxiety disorder. One case
series of nine autistic children, aged 6–12 years, docu-
ments improvement in anxiety, irritability, and agitation
with clinical response to low doses (25–50 mg/day)
appearing generally in 2–8 weeks and, frequently, wan-
ing after a few months (Steingard et al., 1997). Hence,
short-term sertraline treatment can reduce behavioral
reactions associated with situational transitions or envi-
ronmental changes in children with ASD, though bene-
ficial effects may be temporary. An open-label study
showed significant improvement in repetitive and
aggressive symptoms, but not in social deficits, in
24 of 42 (57%) adults with ASD (McDougle et al.
1998). The most common adverse effects were weight
gain, anxiety, and psychomotor agitation. There is only
one open-label study on 28 ASD children treated with
escitalopram, reporting significant improvement in
CGI-I ratings and in ABC scores for irritability, lethargy,
stereotypy, hyperactivity, and inappropriate speech.
Dose-related adverse effects, notably irritability and
hyperactivity, occurred at doses above 10 mg/day in
78% of cases (Owley et al., 2005).
In summary, SSRIs are definitely more effective in
neurotypical individuals suffering from OCD and
depression than in autistic individuals affected by
396 A.M. PERSICO ET AL.
obsessive and anxious–depressive symptoms. Second, reducing inappropriate sexual behavior associated with
they appear relatively more effective and better tolerated ASD (Nguyen and Murphy, 2001; Albertini et al.,
in adult autistic individuals, as compared to ASD chil- 2006; Coskun and Mukaddes, 2008; Coskun et al.,
dren and adolescents. Nonetheless, a trial with an SSRI 2009). The efficacy of trazodone, a heterocyclic antide-
should be considered whenever compulsive behavior pressant, has been the object of only a few case reports
and anxiety are posing major hurdles to developmental, involving ASD children. One case report showed a
educational, and social progress. A valid trial should last reduction of aggression at a dose of 150 mg/day in
10–12 weeks but, contrary to nonautistic patients, shorter divided doses (Gedye, 1991); another case study
trials (i.e., 1–3 weeks) may suffice and prevent subse- reported beneficial effects of trazodone on sleeping in
quent behavioral activation. Low SSRI doses should an 8-year-old autistic boy also treated with fluvoxamine
be prescribed with frequent clinical monitoring of target (Parker and Hartman, 2002); priapism was described as a
symptoms and potential side effects. dose-dependent side effect in a 13-year-old autistic boy
(Kem et al., 2002).
SEROTONIN AND NOREPINEPHRINE
ANTIANXIETY MEDICATIONS
REUPTAKE INHIBITORS AND OTHER
ANTIDEPRESSANT MEDICATIONS Antianxiety agents such as benzodiazepines have been
relatively understudied in ASD. They are clinically use-
Among serotonin and norepinephrine reuptake inhibitors
ful at times in the treatment of anxiety, particularly as
(SNRIs), more data are available for venlafaxine, which
add-on to an SSRI. However, behavioral side effects such
inhibits the reuptake of serotonin, norepinephrine, and,
as disinhibition, crying, and irritability limit their use.
to a lesser extent, dopamine (Ellingrod et al., 1994). Sig-
Instead, two RCTs have been performed on buspirone,
nificant improvement in repetitive behaviors, restricted
a 5-HT1A receptor agonist. An 8-week RCT involving
interests, social deficits, communication and language,
40 ASD children and adolescents showed that low-dose
inattention, and hyperactivity were reported in an open,
buspirone is more effective than placebo as add-on
retrospective study involving 10 autistic children,
to risperidone for treating irritability (Ghanizadeh
adolescents, and young adults (Hollander et al., 2000).
and Ayoobzadehshirazi, 2015). At a mean dose of
Clinical response was observed at low doses
6.7 mg/day, 13/16 (81.2%) buspirone-treated patients
(6.25–50 mg/day, mean daily dose 24.37 mg) and the
showed a 30% decline in irritability scores compared
drug was well tolerated. Another open trial reported
to 7/18 (38.9%) patients in the placebo group. Contrary
beneficial effects of low-dose venlafaxine on self-injury
to buspirone alone, which tends to decrease appetite and
and hyperactivity in two 17-year-old autistic boys
body weight, the most common adverse effect adding
and in a 23-year-old autistic woman (Carminati et al.,
buspirone onto risperidone was increased appetite, as
2006). A recent RCT found no convincing evidence of
well as drowsiness and fatigue. Another recent multicen-
efficacy, contrasting six patients receiving venlafaxine
ter RCT enrolled 166 ASD preschoolers aged 2–6 years
(18.75 mg/day), along with their usual treatment (zuclo-
randomized to 24 weeks of 2.5/5.0 mg of buspirone twice
penthixol and/or clonazepam), with seven patients who
daily vs placebo (Chugani et al., 2016). No difference in
received placebo plus usual care (Carminati et al.,
ADOS Composite Total Score among the 3 treatment
2016). At the end of the study, global improvement
groups was recorded at 24 weeks, but the ADOS
was observed in 33% and 71% of venlafaxine- and
Restricted and Repetitive Behavior score showed a
placebo-treated patients, respectively, with irritability
time-by-treatment effect: 2.5-mg buspirone produced
improving equally in the entire sample. Only marginal
significant improvement, whereas placebo and 5.0-mg
evidence of lower cumulative doses of clonazepam and
buspirone yielded no change. Adverse events did not dif-
zuclopenthixol in the venlafaxine-treated group was
fer significantly among treatment groups. This study thus
obtained. Mirtazapine, a TCA, acting as an antagonist
supports low-dose buspirone treatment (2.5 mg/day) as
at a2 adrenergic and at multiple serotonin receptors,
an adjunct therapy to target restrictive and repetitive
improved aggressiveness, self-injury, irritability, hyper-
behaviors in conjunction with behavioral interventions.
activity, anxiety, depression, and insomnia in 9 of
26 (34.6%) ASD subjects, according to one open-label
ANTIEPILEPTICS AND MOOD
study (Posey et al., 2001). Mirtazapine did not improve
STABILIZERS
core social and communication deficits. Adverse effects
were minimal and included increased appetite, irritabil- Antiepileptic drugs (AEDs) have been extensively
ity, and transient sedation. Other case reports suggest employed in ASD as mood stabilizers and to attenuate
efficacy for this drug, at a dose ranging from 5 to problem behaviors, but only a limited number of open-
30 mg/day, not only on aggressiveness but also in label studies and RCTs have been performed in autistic
 PSYCHOPHARMACOLOGY OF ASD AND RETT SYNDROME
children and adolescents (Hirota et al., 2014;
Canitano, 2015).
Valproic acid was found to attenuate irritability in an
initial open trial including 14 young ASD patients (with
and without seizures) (Hollander et al., 2001). Three sub-
sequent RCTs enrolling 12–30 ASD subjects yielded
contrasting results (Hellings et al., 2005; Hollander
et al., 2006b, 2010). Hellings et al. (2005) found no sig-
nificant difference in ABC irritability scores, with high
interindividual variability and large placebo effect. On
the contrary, using more severe symptomatic inclusion
criteria to reduce interindividual variability, Hollander
et al. (2010) showed a significant advantage of sodium
divalproex over placebo. Furthermore, Hollander et al.
(2006b) reported significant improvement in repetitive
behaviors in a small RCT involving 13 autistic children.
Valproate was also found to attenuate the irritability asso-
ciated with fluoxetine treatment in ASD significantly
better than placebo (Anagnostou et al., 2006).
Levetiracetam binds to the synaptic vesicle glycopro-
tein SV2A, inhibiting presynaptic calcium channels and
reducing neurotransmitter release. This pharmacologic
action limits nerve signal conduction across synapses
(Lynch et al., 2004; Vogl et al., 2012). The use of levetir-
acetam in ASD is controversial due to several studies
reporting major behavioral side effects. Levetiracetam
was initially found to improve attention, hyperactivity,
emotional lability, and aggressiveness in an open trial
involving six drug-naive ASD boys (Rugino and
Samsock, 2002). Wasserman et al. (2006) compared
levetiracetam to placebo in a sample of 20 ASD children,
aged 5–17 years, and found no evidence of efficacy on
global functioning, irritability, repetitive behaviors,
impulsivity, and hyperactivity. The most relevant side
effect was aggression. Levetiracetam was also found
ineffective for controlling stereotyped movements in
patients with ASD (Rajapakse and Pringsheim, 2010).
Importantly, one case report documents an autistic
regression, characterized by stereotypic behaviors and
severe social and communicative dysfunction after
administration of levetiracetam in a 6-year-old girl with
cerebral palsy, whose main symptoms were mild intellec-
tual disability and focal epilepsy. This regression sub-
sided after drug discontinuation, suggesting that
levetiracetam may occasionally provoke ASD-like
behavioral adverse effects (Camacho et al., 2012).
Finally, 70 children with ASD and subclinical epilepti-
form discharges (SEDs) identified by EEG were ran-
domly divided into two equal groups treated either
with levetiracetam (60 mg/kg/day) and educational train-
ing (treatment group) or with educational training only
(control). At the 6-month follow-up, PEP-3 scores were
significantly higher for the treatment group compared
to controls, whereas CARS and ABC scores were
397
significantly lower (Wang et al., 2017). EEG normaliza-
tion was significantly more frequent in the treatment
group (Wang et al., 2017).
Topiramate is an interesting drug, because of its
weight-containing and mood-stabilizing effects, but the
few studies performed to date have yielded conflicting
results. An 18-month open-trial involving 10 ASD chil-
dren and adolescents undergoing weight gain with SGA
treatment reported modest variation in weight excess and
frequent adverse behavioral effects, dampening enthusi-
asm for topiramate add-on use (Canitano, 2005). Simi-
larly, limited efficacy and frequent side effects were
reported in another case series (Mazzone and Ruta,
2006). However, an 8-week RCT involving 40 autistic
children, 4–12 years old, randomly allocated to receive
either topiramate + risperidone (Group A) or placebo
+ risperidone (Group B), showed beneficial effects for
topiramate on irritability, stereotypic behaviors, hyperac-
tivity, and/or noncompliance (Rezaei et al., 2010). Lamo-
trigine, an AED mainly active in reducing voltage-gated
Na+ currents, showed no efficacy on irritability and
social behavior in an RCT involving 27 autistic children
aged 3–11 years old (Belsito et al., 2001). The use of
oxcarbazepine for irritability and agitation in ASD has
been addressed in only 1 case series, involving
30 patients, aged 5–21 years, taking on average 2 other
psychotropic medications, including SGAs, SSRIs,
alpha agonists, and divalproex (Douglas et al., 2013).
Fourteen patients (47%) achieved a CGI-I score of
“much improved,” while another 10 patients (33%) were
“improved”; 7 patients (23%) had a clinically significant
adverse effect leading to drug discontinuation. Finally, a
recent case report points toward possible beneficial
effects of low-dose phenytoin (5 mg/day for over
18 months) on verbal and nonverbal communication in
a 19-year-old autistic young man treated with stimulant
medication since early childhood (Bird, 2015).
Lithium is a “classical” mood stabilizer also used in
autistic individuals with comorbid recurrent affective
disorder and/or mood instability, especially in the pres-
ence of mania, euphoria, or elevated mood. There are
currently no RCTs of lithium in children and adolescents
with ASD. Two older case reports document the efficacy
of lithium therapy, the first one at blood levels
>1.0 mEq/L on two 4-year-old autistic children with
hyperactivity resistant to stimulant drugs and with cycli-
cal mood swings (Kerbeshian et al., 1987); the second
case report describes a beneficial response to lithium in
two individuals with ASD whose symptoms included
agitation, self–injurious behavior, aggression, and
insomnia (Steingard and Biederman, 1987). In a more
recent retrospective chart review of 30 children and ado-
lescents with ASD treated with lithium because of
comorbid bipolar disorder, 43% were rated as improved
398 A.M. PERSICO ET AL.
on CGI-Irritability scores and 71% of patients with two
or more pretreatment mood disorder symptoms were
rated as improved (Siegel et al., 2014). Patients most
improved were those with mania and elevated mood.
Mean lithium blood level was 0.70 mEq/L, and the mean
duration of lithium treatment was 29.7 days. At least one
adverse effect was reported by 47% of patients, most
commonly vomiting (13%), tremor (10%), fatigue
(10%), irritability (7%), or enuresis (7%) (Siegel
et al., 2014).
A very interesting case report describes the efficacy of
lithium as a rescue therapy for regression and catatonia and
autistic traits in a 21-year-old man and in a 17-year-old girl
with Phelan–McDermid syndrome, due to chr 22q13.33
deletion involving the SHANK3 gene (Serret et al.,
2015). The former patient, unresponsive to multidrug ther-
apies including antipsychotics and other psychotropic
drugs, responded to 1500 mg/day of lithium, yielding
blood levels of 0.8 mEq/L. Lithium successfully corrected
a severe regression characterized by increasing psycho-
motor agitation, aggressiveness, impulsivity, urinary, and
bowel incontinence, promoting cognitive and social
improvement over the subsequent 3-month period. The
latter patient underwent a period of severe behavioral
regression and catatonia. One year of lithium treatment
(1000mg/day, lithium blood level 0.7 mEq/L), in associa-
tion with a low dose of clonazepam (0.2 mg/day), spurred
improvement in motor and verbal abilities allowing the
patient to recover to similar levels of functioning as
before regression. In both cases lithium was well tolerated.
Another case report is on an adult male with Phelan–
McDermid syndrome whose mood and behavior
responded to a combined treatment with lithium and olan-
zapine, following resistance to various combinations of
SGAs and AEDs (Egger et al., 2017).
Future prospective studies of lithium are needed to
assess whether lithium strictly benefits comorbid bipolar
symptoms or improves some ASD-specific symptoms.
STIMULANTS AND a2 ADRENERGIC
AGONISTS
The comorbidity between ASD and ADHD, now recog-
nized by DSM-5, is present in 30%–40% of autistic indi-
viduals (Berenguer-Forner et al., 2015). This high
incidence and the negative impact of inattention, hyper-
activity, and impulsivity on treatment programs and on
social adjustment, have spurred interest in the use of psy-
chostimulants in ASD patients with comorbid ADHD.
Methylphenidate (MPH) acts as a dopamine and, to a
lesser extent, as a norepinephrine reuptake blocker. It
is the psychostimulant most prescribed for children with
ADHD. In general, MPH is known to be moderately
efficacious in improving ADHD symptoms in ASD,
possibly more in children than in adults. However,
response rates tend to be somewhat lower, and adverse
effects more frequent, in autistic individuals compared
to typically developing children with ADHD
(RUPPAN, 2005b). Interindividual variability in
response to MPH by autistic children may be influenced
by multiple monoaminergic gene variants (McCracken
et al., 2014). Six RCTs of MPH in children with ASD
have been performed to date. In the initial RUPPAN
study (2005b), 66 of 72 children, aged 5–14 years, with
a DSM-IV diagnosis of Autistic Disorder or Pervasive
Developmental Disorder-Not Otherwise Specified
(PDD-NOS) were randomized to a double blind cross-
over study of MPH vs placebo. A significant improve-
ment was recorded on the ABC hyperactivity subscale,
with 49% of participants responding at all MPH dose
increments and maximum benefits at medium-high doses
(0.25 and 0.5 mg/kg per dose, respectively). Improve-
ment in hyperactivity/impulsivity and inattention, with-
out significant worsening of stereotypic or oppositional
defiant behavior, was later confirmed in the same sample
using other outcome measures, such as SNAP-IV and
CY-BOCS scores (Posey et al., 2007), with improvement
again most evident at 0.25–0.50 mg/kg doses. The most
common adverse effects of MPH included irritability,
appetite loss, insomnia, and emotional outbursts. Similar
results were obtained in other RCTs involving autistic
children (Quintana et al., 1995; Handen et al., 2000;
Jahromi et al., 2009). Dosage for ASD children ranges
from 7.5 to 50 mg/day, sometimes divided and often
dosed by weight (0.3–0.6 mg/kg/day); for preschool chil-
dren ranges between 5 and 20 mg/day in divided doses
(Doyle and McDougle, 2012). A 4-week RCT conducted
by Pearson et al. (2013) in 24 ASD children, with mean
age 8.8 years and comorbid ADHD, demonstrated ben-
eficial effects on hyperactivity, with the combination
of extended-release MPH in the morning and
immediate-release MPH in the afternoon. This study is
especially interesting, because this combination is fre-
quently applied in clinical practice. In a recently pub-
lished RCT (Kim et al., 2017), 27 subjects, aged 5–17
years with ASD and ADHD, were randomized to receive
either low (10 mg/day) or medium (30 mg/day) doses of
an extended-release liquid formulation of MPH. Signif-
icant decreases in irritability and hyperactivity ABC
scores were recorded more frequently in the medium
dose group (mean dose ¼ 20.28 mg/day). Also, rebound
hyperactivity and aggression at the end of the day were
significantly lower only in the medium-dose group.
In several studies, and also in clinical practice, intel-
lectual disability and lower IQ tend to be associated with
lower response rates to MPH and with more side effects
(Aman et al., 2003). However, at least 1 RCT involving
122 children and adolescents with severe ADHD and
 PSYCHOPHARMACOLOGY OF ASD AND RETT SYNDROME
intellectual disability (including many with comorbid
ASD) found MPH (0.5/1.0/1.5 mg/kg/day) significantly
superior to placebo and no correlation between IQ
or ASD symptoms and clinical response (Simonoff
et al., 2013).
Atomoxetine is a selective dopamine and norepineph-
rine reuptake inhibitor, approved for the treatment of
ADHD in children, adolescents, and adults starting at
6 years of age. A 4-week RCT performed on 97 ASD
individuals with comorbid ADHD, aged 6–17, found
some evidence of efficacy for atomoxetine (1.2 mg/kg/
day) on hyperactivity, stereotyped behaviors, inappro-
priate speech, and fear of change, but no significant
global improvement using the CGI; side effects included
nausea, decreased appetite, fatigue, and early morning
awakenings (Harfterkamp et al., 2012). A subsequent
open-label follow-up study conducted on 88 patients
taking the drug for 28 additional weeks showed impro-
vement in hyperactivity, impulsivity, and inattention
(Harfterkamp et al., 2013). Adverse events, including
gastrointestinal symptoms, irritability, tinnitus, mood
swings, and sedation, were generally mild and tended
to diminish over time, especially nausea and fatigue.
Dosages generally ranged from 1.2 to 1.4 mg/kg/day.
Another recent RCT in 128 ASD children (ages 5–14)
lasting 6 weeks for dose adjustment based on clinical
response (up to a maximum of 1.8 mg/kg/day), followed
by dose maintenance for an additional 4 weeks, con-
firmed that: (a) the most frequent side effects are
decreased appetite and fatigue, (b) most side effects do
not raise concern and last 4 weeks of less, and
(c) unlike typically developing children, ASD children
did not display serious adverse events, including QTc
changes or suicidal ideation (Tumuluru et al., 2017).
An interesting recent RCT demonstrates the effective-
ness of atomoxetine over placebo, underscoring at the
same time the usefulness of parent training in the context
of an effective multidisciplinary treatment approach. In
particular, the combination of atomoxetine + parent train-
ing (ATX + PT) produced higher response rates with
lower atomoxetine doses compared to the doses pre-
scribed in the “atomoxetine alone” group. Meanwhile,
ATX + PT and ATX alone were superior to placebo
+ PT and to placebo alone, respectively, in improving
ADHD symptoms (Handen et al., 2015). A subsequent
24-week extension study involving 117 children, aged
5–15, out of the 128 (91%) acute-trial participants, con-
firmed the efficacy of atomoxetine, providing further evi-
dence of the greater benefits obtained by combining
pharmacologic and psychosocial treatments over either
treatment alone, both in terms of treatment outcome
and patient compliance (Smith et al., 2016).
An open-label trial of 11 children with ASD explored
the safety and efficacy of reboxetine, a selective
399
norepinephrine reuptake blocker, in reducing depressive
and inattentive/hyperactive symptoms (Golubchik et al.
2013). A significant, yet modest, decrease in the severity
of depressive and ADHD symptoms assessed with
CDRS and ADHD-RS, respectively, was recorded.
A significant positive correlation was found between
changes in depression and ADHD severity scores. Most
patients reported minimal or tolerable side effects.
Clonidine is a selective a2 adrenergic and
imidazoline-1 receptor agonist, approved by the FDA
in 2010 for the treatment of ADHD in pediatric patients
starting at age 6. Two RCTs provided evidence of effi-
cacy on impulsivity, hyperarousal, and self-stimulating
behavior in ASD children and adults (Fankhauser
et al., 1992; Jaselskis et al., 1992). This drug is also effec-
tive on hyperactivity, aggressiveness, mood instability,
irritability, and on nighttime awakenings, improving
sleep quality (Ming et al., 2008). In these studies, drug
dosage ranges from 0.1 to 0.2 mg/day and side effects
included drowsiness, sedation, hypertension, and
decreased activity. Guanfacine is a central a2 adrenergic
agonist. A retrospective study of 80 ASD children and
adolescents, aged 8–18 years, reported improvement in
hyperactivity, inattention, insomnia, and tics (Posey
et al., 2004a). An open trial found 12 out of 25 (48%)
ASD children, either nonresponders or intolerant to
MPH, responded well to guanfacine (Scahill et al.,
2006). The efficacy of this drug in improving hyperactiv-
ity in ASD children was then confirmed by two RCT
studies (Handen et al., 2008; Scahill et al., 2015). Dos-
ages ranged between 0.25 and 9 mg/day, often in divided
doses. The most frequent side effects included irritability,
drowsiness, decreased energy, sleep disturbance, consti-
pation, headache, and nocturnal enuresis (Handen et al.,
2008; Scahill et al., 2015).
FUTURE PERSPECTIVES IN THE
PHARMACOTHERAPY OF AUTISM
SPECTRUM DISORDER
The lack of psychoactive drugs able to ameliorate the
“core” symptoms of ASD is currently felt as perhaps
the main unmet need in pediatric neuropsychophar-
macology (Persico et al., 2015). For this reason, an
impressive effort is being put forth by academia and
pharmaceutical companies to move the field of autism
psychopharmacology forward. No other behavioral
disorder of childhood and adolescence is the target of
as many ongoing clinical trials listed on the NIH web
site https://clinicaltrials.gov/. Some experimental drugs
derive from animal and human research on monogenic
forms of syndromic autism, for example, Rett syndrome,
fragile X, tuberous sclerosis, and Phelan–McDermid
syndrome, among many. Other drugs derive from
400 A.M. PERSICO ET AL.
cellular, animal, molecular, and human studies of idio-
pathic ASD, whose pathogenetic underpinnings are
beginning to be relatively well understood. Drugs
derived from research on syndromic forms were initially
spurring high expectations, because in mouse models
they displayed a surprising degree of effectiveness when
administered not only prenatally, but also postnatally or
even in adult animals. Unfortunately, these drugs have
not met their primary endpoints in human RCTs, once
again proving that animal and cellular models can indeed
contribute preliminary but never conclusive evidence of
efficacy, given the exquisite complexity of the
human brain.
On the other hand, among drugs derived from patho-
genetic studies of idiopathic ASD, some may display
measurable efficacy on core ASD symptoms, although
with different levels of evidence. We hereby summarize
the most studied and/or the most promising pharma-
cologic agents in the experimental pipeline for the
treatment of core autistic symptoms:
Oxytocin and vasopressin
Oxytocin and arginine-vasopressin, synthesized by the
magnocellular neurons of the supraoptic nucleus and
the magnocellular and parvocellular neurons of the para-
ventricular hypothalamic nucleus, in addition to
“classic” hormonal functions, also act as neurotransmit-
ters, released in extrahypothalamic regions. Dense
expression of oxytocin receptors (OXTR) is present in
regions critical to social cognition, attachment, empathy,
and motivation, such as the anterior cingulate cortex, the
temporo-parietal junction, the insula, and the nucleus
accumbens, while AVPR1a receptors are expressed in
the hippocampus and the amygdala (Kirsch et al.,
2005; Knafo et al., 2008; Insel, 2010; Meyer-
Lindenberg et al., 2011; Wigton et al., 2015). The
“social role,” mediated by OXTR and the AVPR1a recep-
tors for oxytocin and vasopressin, respectively, was
discovered while studying the differences in attachment
between prairie and mountain voles, two different
rodents species, which show strong and weak attach-
ment, respectively, linked to differential brain OXTR
and AVPR1a gene expression in limbic regions (Carter
et al., 1995; Insel, 2010; Johnson and Young, 2015;
Johnson et al., 2016). Oxytocin and vasopressin thus
act, in females and males, respectively, as critical medi-
ators of maternal, social, and mating behaviors (Lucht
et al., 2009; Insel, 2010; Johnson and Young, 2015).
Not surprisingly, much evidence supports the contribu-
tion of a dysfunctional oxytocin–vasopressin system to
the pathogenesis of ASD (Jacob et al., 2007; Gregory
et al., 2009; Yamasue et al., 2009; Zhang et al., 2017).
Both oxytocin and vasopressin have a short half-live
of around 3 min in plasma and 20 min in CSF, where they
are inactivated by placental leucine aminopeptidase
(LNPEP) (Gazis, 1978). Therefore, only through the
nasal route is it possible to ensure that a substantial
amount of the active ingredient reaches the CNS, given
its peptide nature and half-life; in fact, if this therapy was
administered parenterally, only 1% of these neuropep-
tides would reach the CNS unmodified.
Based on these data, intranasal oxytocin and vaso-
pressin, as well as the AVPR1a antagonist RG7314,
are under scrutiny. Intranasal oxytocin, certainly the most
studied compound in current experimental ASD pharma-
cology, yields insufficient evidence of efficacy on core
ASD symptoms, according to two recent meta-analyses
including 17 and 12 RCTs, respectively (Keech et al.,
2017; Ooi et al., 2017). Given the genetic variability of
the OXTR gene and anatomical differences in nasal cav-
ity influencing oxytocin absorption into the CNS, this
interindividual variability in response to intranasal
oxytocin in ASD is not surprising.
Bumetanide
Bumetanide is a selective diuretic for Cl, acting as a
high affinity antagonist for the NKCC1 transporter
(Feit, 1981). The transmembrane Cl gradient is pro-
duced by the activity of two cotransporters, NKCC1
importing Cl into the cell, and KCC2 extruding Cl into
the extracellular space (Payne et al., 2003). In the adult
brain, Cl is more concentrated in the extracellular fluid,
due to KCC2 being more expressed than NKCC1, so that
the opening of GABA-A channels produces Cl entry
into the neuron and hyperpolarization. Instead, during
prenatal and early postnatal life, NKCC1 is more
expressed than KCC2, inverting the Cl gradient and
causing depolarization when GABA-A channels open
(Ben Ari et al., 2007). In neurodevelopmental disorders
like autism, intellectual disability, and epilepsy, this
immature configuration often persists at later ages also,
contributing to the excess of excitation over inhibition
present in ASD and causing the so-called “paradoxical
effect” of benzodiazepines, i.e., a pharmacologic induc-
tion of psychomotor agitation instead of anxiolysis and
sedation (Marrosu et al., 1987). Bumetanide aims to
reduce this imbalance, by promoting Cl outflow from
excitable neurons through renal excretion.
One open-label study conducted on eight teenagers
with ASD initially provided promising results. Bumeta-
nide led to improvement in the ability to recognize and
characterize the emotions expressed by the face follow-
ing an activation of the brain regions involved in facial
recognition and social and emotional perception, such
as the fusiform gyrus and the inferior occipital gyrus
 PSYCHOPHARMACOLOGY OF ASD AND RETT SYNDROME
(Hadjikhani et al., 2015). Two subsequent RCTs pro-
duced significant improvement of autistic behaviors
measured using the CARS, SRS, and CGI; parents
defined their children as “present,” with a greater capac-
ity for integration and communication with the environ-
ment, signaling few side effects (Lemonnier et al., 2012,
2017). Maximum efficacy was recorded at the dose of
1 mg twice a day, maximum safety at 0.5 mg b.i.d. The
most frequent adverse events were hypokalemia, enure-
sis, dehydration, appetite loss, and muscle weakness
(Lemonnier et al., 2017).
Sulforaphane
Sulforaphane is a natural compound especially present in
broccoli sprouts, endowed with antioxidant and antineur-
oinflammatory effects. An initial RCT showed sizable
improvement in ABC scores for irritability, lethargy, ste-
reotypies, and hyperactivity, as well as in SRS scores for
awareness, communication, motivation, and mannerisms
(Singh et al., 2014). Beneficial effects on social interac-
tion, aberrant behaviors, and verbal communication were
recorded using the CGI-I. The substance was very well
tolerated and this substance is currently being tested in
several ongoing RCTs (Singh et al., 2014).
Glutamatergic drugs: Memantine and
D-cycloserine
D-Cycloserine acts as a partial agonist of the glycine
binding site at NMDA receptors. By modulating glycine
action as a cotransmitter at the NMDA receptor, this drug
is predicted to promote longer channel openings with
increased Ca2+ entry, ultimately enhancing connectivity
and consolidating environmentally induced plastic mod-
ifications in excitatory circuits. An initial single-blind
pilot study in 10 autistic patients showed a significant
improvement in social withdrawal (Posey et al.,
2004b). Two subsequent RCTs (Urbano et al., 2014,
2015; Minshawi et al., 2016; Wink et al., 2017) have
shown significant clinical improvement in core ASD
symptoms (Urbano et al., 2015) as well as in stereotyped
behaviors (Urbano et al., 2014), with a synergistic effect
in behavioral intervention, fully compatible with the
activity-mediated mechanism of action of this drug.
The only frequent side effect was a modest increase in
irritability.
Memantine acts as a noncompetitive low-affinity
NMDA receptor antagonist (Chen et al., 1992;
Kornhuber et al., 1989). Its short-lived receptor blockade
kinetics prevents negative effects on learning and mem-
ory (Lipton, 2006; Danysz and Parsons, 2012). Its bene-
ficial effects on synaptogenesis and neural networking,
demonstrated in different animal and cellular models,
led to several prospective and retrospective open-label
401
studies, suggesting beneficial effects on social interac-
tion and sensory self-stimulation (Rossignol and Frye,
2014b). Two RCTs published to date have given contra-
dictory results, but the two studies differ substantially in
many regards. A study on 121 children and teenagers
with ASD did not provide evidence of efficacy, although
tolerability was found to be reassuring (Aman et al.,
2017). On the contrary, the addition of memantine to ris-
peridone in 40 autistic children showed further improve-
ment in irritability, stereotypies, and hyperactivity
(Ghaleiha et al., 2013). Additional studies are ongoing
to test memantine effects on memory, communication
and spoken language, motor skills, problem behaviors,
and cognition in ASD.
Arbaclofen (STX209)
The known imbalance between excitatory and inhibitory
neurotransmission, as well as studies clarifying the com-
plex interface between GABA-B, mGluR5 and AMPA
receptors in the pathophysiology of fragile-X syndrome,
have created interest in arbaclofen, the prodrug precursor
of the GABA-B receptor agonist R-baclofen (Silverman
et al., 2015), but having greater stability and
manageability.
In a first open study, 32 autistic children and teenagers
received 10 mg of arbaclofen a day (6–11 years) or 10 mg
three times a day (12–17 years). A significant decrease
in irritability and social withdrawal, paired with an
increase in motivational drive towards social interaction,
was observed in approximately half of the sample
(Erickson et al., 2014). A subsequent RCT, however,
did not achieve its primary outcome (social withdrawal
ABC scores) (Veenstra-VanderWeele et al., 2017),
although secondary outcomes on severity, assessed with
the CGI-S and the VABS-II, gave a positive result. Side
effects were mild (emotional lability and drowsiness). As
methodological limitations may have had a negative
impact on this study, further studies are ongoing.
Supplements and probiotics
A variety of supplements have been clinically assessed,
under the assumption that ASD children may benefit
from natural substances endowed with antioxidant, anti-
inflammatory, energy-stimulating, or sleep inducing
properties. Although the methodological quality of RCTs
in natural medicine does not always meet minimum stan-
dards of reliability, it is worth briefly listing the major
areas of interest, as some clinically useful applications
may well come forth in the near future.
● Antioxidants: N-acetylcysteine (NAC), carnosine,
vitamin B12, folinic acid, methyl-B12, glutathione.
These substances should help counteract the
402 A.M. PERSICO ET AL.
accumulation of reactive oxygen species (ROS) pre-
sent in ASD individuals (Kern and Jones, 2006).
RCTs have provided conflicting results for most of
these substances and primary outcome measures do
not usually show a statistically significant effect.
Interestingly, folinic acid may improve language,
attention, and stereotypical behaviors specifically
in ASD children carrying autoantibodies capable of
binding or blocking the FRa receptor (Frye et al.,
2013; Ramaekers et al., 2013). Hence, targeted
patient populations may well benefit from these
compounds.
● Energizers: Q10 ubiquinol and L-carnitine. Coen-
zyme Q10 is a key element in the mitochondrial
respiratory chain. Q10 ubiquinone is reduced to
Q10 ubiquinol in the liver, and the latter represents
the active compound, able to exert an important anti-
oxidant action and to stimulate energy metabolism.
At least two RCTs have assessed the effect of Q10
ubiquinone in 20 and 55 children with ASD, aged
between 5 and 16 years, and shown improvements
on the Parental Global Impressions-Revised scale
as well as in subscales for hyperactivity, opposition,
and receptive language. Unfortunately Q10 ubiqui-
none was administered in the context of multivitamin
and mineral supplements such NAC, choline, and
inositol, complicating the interpretation of these
results (Adams and Holloway, 2004; Adams et al.,
2011). Carnitine allows the transport of fatty acids
across the inner mitochondrial membrane, stimulating
the production of ATP. Blood levels of carnitine would
be reduced in some patients with ASD (Filipek et al.,
2004), and 1 RCT involving 34 ASD children aged
3–10 years showed significant improvement in core
autistic symptoms with supplementation, reporting
only minimal side effects, such as irritability and
intestinal discomfort (Geier et al., 2011).
● Neuroinflammation and autoimmunity: minocycline,
luteolin, and quercetin, omega-3 fatty acids. Neu-
roinflammation is an active mechanism in the CNS
of autistic individuals from relatively early ages
(Vargas et al., 2005; Garbett et al., 2008). Also, auto-
immunity appears to enhance ASD severity in some
patients (Piras et al., 2014). Minocycline, a semisyn-
thetic derivative of tetracyclines with neuroprotec-
tive and antiinflammatory effects, has not shown
significant efficacy in a pilot open-label study
(Pardo et al., 2013). A subsequent RCT of minocy-
cline as add-on therapy to risperidone has yielded
modest improvements (Ghaleiha et al., 2016). Luteo-
lin and quercetin, flavonoid compounds that are sec-
ondary metabolites of plants and present in various
foods, are endowed with powerful antioxidant and
antiinflammatory actions, especially on mast cells
(Kempuraj et al., 2008; Kritas et al., 2013). At least
three open-label studies from the same group have
yielded promising results in ASD children and ado-
lescents, especially in eye contact, attention, social
deficits, problem behaviors, and adaptive skills
(Theoharides et al., 2012; Taliou et al., 2013;
Tsilioni et al., 2015). These results still await confir-
mation by RCTs. Finally, o-3 fatty acids are potent
antiinflammatory and immunoregulatory agents
used in the treatment of a wide variety of diseases
associated with chronic inflammation. According
to a recent meta-analysis of 6 international RCTs,
including 194 autistic patients, the data indicate an
improvement in hyperactivity, lethargy, and stereo-
types, but no effects on global functioning or on
socialization and communication deficits (Cheng
et al., 2017).
● Sleep-inducing agents: melatonin. Sleep distur-
bances are especially frequent in ASD and may be
related to reduced melatonin synthesis and enhanced
kynurenine pathway activation due to neuroinflam-
mation (Gevi et al., 2016). Melatonin, quite possibly
the most widely prescribed compound for the man-
agement of autistic children, may thus represent
more a “substitution” therapy than a pharmacologic
intervention. Seven RCTs have proven melatonin
effective in ameliorating total sleep duration and
sleep onset latency (Rossignol and Frye, 2014a).
Similar improvements were recorded using
prolonged-release melatonin, according to one
recent RCT involving 125 ASD children and adoles-
cents (Gringras et al., 2017).
● Gut-modifying agents. Probiotics are live microor-
ganisms that can stabilize the mucosal barrier by
increasing the expression of mucin, reducing exces-
sive bacterial growth, stimulating mucosal immunity
(secretory IgA), and synthesizing antioxidant sub-
stances (Fond et al., 2015). The high prevalence of
gastrointestinal disorders in ASD, the significantly
skewed gut microbiome found in many autistic chil-
dren, and the interesting results obtained in animal
models with probiotics (Buie et al., 2010; Hsiao
et al., 2013; Tomova et al., 2015) led to interest in
testing probiotics for clinical efficacy in ASD. To
date, evidence of their efficacy is still limited to sev-
eral open trials reporting benefits at the gastrointes-
tinal and/or behavioral level (Adams et al., 2011;
Kaluzna-Czaplinska and Blaszczyk, 2012; Grossi
et al., 2016; Kang et al., 2017; Shaaban et al., 2017).
RETT SYNDROME
The pharmacologic therapy of Rett syndrome is
described here, because this monogenic disorder
 PSYCHOPHARMACOLOGY OF ASD AND RETT SYNDROME
represents an important example of syndromic autism.
Rett syndrome (RTT, OMIM #312750) is an X-linked
neurodevelopmental disorder, which mostly affects
females, although a few cases of RTT males with an extra
X-chromosome or somatic mosaicism have also been
described (Moog et al., 2003). Occurring in
1:10,000–15,000 live female births, it accounts for up
to 10% of severe intellectual disability of genetic origin
in females (Burd et al., 1991; Armstrong, 1997). In clas-
sical RTT, an initial period of normal neurologic and
physical development is followed by partial or complete
loss of acquired purposeful hand skills and speech,
accompanied by gait abnormalities and stereotypic hand
movements. Several stages are observed clinically: stag-
nation (age 6–18 months), rapid regression (age 1–4
years), pseudostationary (age 2–potentially life), and late
motor deterioration (age 10–life). Consequently an RTT
diagnosis is excluded in the presence of grossly abnormal
psychomotor development observed during the first six
months of life, a history of brain injury secondary to
trauma, neurometabolic diseases, or severe neurologic
infections (Neul et al., 2010). Other frequent symptoms
include breathing dysfunction, seizures, spasticity, scoli-
osis, sleep disturbance, and reduced growth (Chapleau
et al., 2013). Atypical forms include the preserved speech
variant initially described by Zappella et al. (2001), char-
acterized by constant intellectual disability, quite often
obesity, and disappearance of hand washing stereotypic
behaviors after the first few years of life. Rare cases of
isolated hypotonia and developmental delay or
Angelman-like clinical presentations have been reported
(Watson et al., 2001; Heilstedt et al., 2002)
RTT is caused mainly by de novo mutations in the
methyl-CpG-binding protein 2 (MECP2) gene, located
on the Xq28 chromosome (Amir et al., 1999). MECP2
plays an important role in neuronal development, den-
dritic branching, and brain morphology, because of its
ability to bind methylated DNA and to orchestrate epige-
netic control over transcription by modulating chromatin
structure in neuronal cells (Lombardi et al., 2015).
Recent studies establish that approximately 95% of clas-
sical RTT cases and 75% of atypical RTT cases have
mutations in MECP2 (Percy et al., 2007; Neul et al.,
2008; Gold et al., 2018). The remaining cases are due
to other genes associated with RTT, including cyclin-
dependent kinase-like 5 (CDKL5), Forkhead box protein
G1 (FOXG1), myocyte-specific enhancer factor 2C
(MEF2C), and transcription factor 4 (TCF4) (Armani
et al., 2012; Gold et al., 2018).
Therapeutic approaches
There are currently no specific pharmacologic therapies
for RTT patients, only those directed at symptomatic
403
control. Often, RTT comes with many associated comor-
bidities, which complicate patient management and
require a multidisciplinary intervention (Tarquinio
et al., 2015). Cognitive decline, breathing dysfunction,
epileptic seizures, spasticity, scoliosis, and reduced
growth are some of the most frequent symptoms that
emerge at the time of developmental regression.
Recent projections estimate that RTT patients will live
into adulthood (Kirby et al., 2010). It is thus necessary to
provide a complete assessment of the symptoms that
most frequently occur in these patients, in order to choose
the best therapeutic options. Our improved understand-
ing of the pathophysiologic underpinnings of RTT has
stimulated research into better treatment for comorbid
symptoms and the development of new compounds that
are potentially able to boost compensatory mechanisms.
We now briefly review pharmacologic interventions
targeting neurologic and psychiatric symptoms associ-
ated with RTT, as well as the main drugs currently
undergoing clinical trials for this syndrome.
The pharmacology of sleep, breathing,
psychiatric, and behavioral disturbances
Sleep disturbances are relatively common in RTT, reach-
ing over 60% of cases (Anderson et al., 2014). Before
prescribing treatments to regulate circadian rhythmicity,
clinicians should exclude abdominal pain, gastroesoph-
ageal reflux, and airway obstruction as possible contrib-
utors. RTT patients typically suffer from initial and/or
intermediate insomnia, i.e., difficulty falling asleep and
frequent awakenings during the night, respectively
(Piazza et al., 1990). Appropriate sleep hygiene is impor-
tant in RTT patients, but pharmacologic treatments can
be helpful. The most frequently prescribed sleep inducer
is melatonin, which has been found to ameliorate also
total sleep duration and sleep quality in a small 4-week
RCT trial on nine RTT young girls (McArthur and
Budden, 1998). Also L-carnitine may improve sleep
duration and quality, according to 1 case report of carni-
tine deficiency in a 5-year-old Rett girl (Plochl et al.,
1996) and 1 open trial involving 21 Rett girls (Ellaway
et al., 2001).
Psychiatric symptoms are also emerging as a major
concern in RTT, because they are frequent and often
difficult to diagnose. These include anxiety, mood distur-
bances, and disruptive behaviors. Mood and anxiety dis-
orders may be slightly more prevalent in RTT individuals
aged 26–30 years, compared to younger and older age
groups (Anderson et al., 2014). According to three case
reports (G€okben et al., 2012; Brook and Usman, 2015;
Ohno et al., 2016), the most effective drugs used to man-
age anxiety, mood disturbances, self-aggressiveness,
and sleep apneas are SSRI antidepressants, often in
404 A.M. PERSICO ET AL.
association with the 5-HT1A agonist buspirone or similar
compounds (G€ okben et al., 2012; Brook and Usman,
2015; Ohno et al., 2016). In RTT rodent models, these
compounds interestingly induce MECP2 gene expres-
sion, regulate CO2 chemosensitivity, and modulate the
hypothalamic–pituitary–adrenal axis, which is fre-
quently altered in RTT patients (Hesketh et al., 2005;
Cassel et al., 2006; Toward et al., 2013). Breathing dis-
orders, including hyperventilation, apnea, breath hold-
ing, and air swallowing, are much more frequent while
awake, but may also occur during sleep and deserve a
trial with the above-mentioned serotoninergic agents,
while the tricyclic antidepressant desipramine has proven
clinically ineffective in an RCT involving 36 RTT girls
(Mancini et al., 2017).
The pharmacology of epilepsy
As many as 60%–80% of RTT patients develop seizures
that evolve into epilepsy, typically at the end of the
regression period or soon afterward. RTT is not associ-
ated with any specific seizure type. In a substantial pro-
portion of individuals with RTT, epilepsy is considered
the major clinical concern, especially in reference to
treatment strategies (Glaze et al., 2010; Nissenkorn
et al., 2015). AED treatment is currently based on the
general epilepsy literature and on clinical experience,
since prospective studies are difficult to perform, given
the relatively low prevalence of this rare disease
(Huppke et al., 2007; Krajnc et al., 2011; Pintaudi
et al., 2015). AEDs shown to be effective in seizure man-
agement and control include valproate (VPA), carbamaz-
epine (CBZ), and oxcarbamazepine, with additional case
reports supporting lamotrigine (LTG), levetiracetam, and
topiramate (Krajnc, 2015). Many RTT patients present
serious adverse events and/or suffer from drug-resistant
seizures. VPA may be most effective in younger girls,
with satisfactory seizure control in 40% of the patients
aged <5 years and in 19% of the girls aged 5–9 years,
while CBZ may be the most effective AED in patients
15 years or older, followed by LTG, which is prescribed
less frequently due to nutritional and behavioral side
effects (Vignoli et al., 2017). The prevalence of drug-
resistant epilepsy in RTT patients reaches approximately
30%, as occurs with other newly diagnosed epilepsies,
and another 20%–40% become refractory to treatment
over time (Krajnc, 2015).
The pharmacology of gastrointestinal
dysfunction
Gastrointestinal problems are common and often severe
in RTT patients. They include gastroesophageal reflux,
air swallowing with abdominal distention, chronic con-
stipation, and abdominal pain, occasionally due to
gallbladder disease (Motil et al., 2012; Freilinger et al.,
2014). Several nonpharmacologic methods can be used
to aid or prevent these symptoms, but proton pump inhib-
itors and the H2 receptor blocker ranitidine remain a
viable option, provided drug–drug interactions and the
need for vitamin D treatment are carefully considered
(Chapleau et al., 2013).
Adaptive and behavioral training
The regression phase of RTT typically encompasses loss
of previously acquired language skills and of purposeful
hand use, increasing difficulties in motor abilities (dys-
praxia), and intellectual disability. Hence, behavioral
training based on the general principles of operant
conditioning represents one of the two major areas of
intervention with RTT patients. The second area is repre-
sented by alternative communication strategies. Similar
to patients diagnosed with ASD, during the regression
period RTT patients display deficits in social contact
and experience communication dysfunction. However,
social deficits and eye contact progressively improve
in the following years, allowing nonverbal communica-
tion with caregivers, provided some training and facilita-
tion is given. The development of novel augmentative
communication technologies has allowed otherwise non-
verbal RTT patients to engage with others and to express
themselves (Townend et al., 2016), promoting social
adaptation of RTT young adults into their families and
enjoyment of interpersonal contact (Haas, 1988). Addi-
tional cognitive approaches employ nonverbal training
aimed at teaching basic and complex emotion recogni-
tion as part of a cognitive rehabilitation program
(Fabio et al., 2013). Also motor learning supplemented
with social, cognitive, and other sensory experiences
has been proven useful (Rodger et al., 2018).
Experimental pharmacologic treatments
Following the discovery of MeCP2 roles in RTT, many
research projects aimed at identifying potential therapeu-
tic targets in RTT have been conducted. At the moment,
the most achievable strategy for treating “classical” RTT
seems to target events downstream from the MeCP2 def-
icit (Kaufmann et al., 2016). Following this approach, as
seen for ASD, ongoing trials are testing omega-3 fatty
acids, to reduce oxidative stress (Leoncini et al., 2011);
folinic acid to restore methylation capacity (Hagebeuk
et al., 2011); lovastatin (NCT02563860) and drugs like
EPI-743 and triheptanoin to improve metabolic and
mitochondrial function, respectively; glatiramer acetate
and fingolimod, synaptic regulators, and BDNF-
enhancers; dextromethorphan and ketamine (Chapleau
et al., 2013; Gupta et al., 2014), NMDA receptor antag-
onists possibly able to counteract the excess NMDA
 PSYCHOPHARMACOLOGY OF ASD AND RETT SYNDROME
receptor density documented in MeCP2 knockout mice
(Blue et al., 2011), and the excess glutamate present in
the CSF of young RTT girls (Hamberger et al., 1992).
Bromocriptine and desipramine have also been studied
for their effect on monoamine neurotransmitters
(Zappella et al., 1990), based on clinical signs of
impaired dopaminergic activity in RTT (Humphreys
and Barrowman, 2016). Initially among the most prom-
ising compounds, IGF1 (mecasermin) is a pleiotropic
growth factor with critical roles in synapse development,
maturation, and maintenance. IGF1 is able in vitro to
counteract the most evident functional outcome of the
loss of MeCP2 at the neuronal level, namely loss of den-
drite ramifications, decreased number of dendritic spines
and reduced synaptic contacts. One open trial involving
10 Rett girls treated with IGF1 twice a day subcutane-
ously for 20–24 weeks, compared to 10 untreated
patients, examined IGF-1 for efficacy, safety, and toler-
ability (Pini et al., 2016). A statistically significant
improvement in several measures of Rett severity and
social adjustment was obtained, but changes were far less
impressive than those recorded in rodent models. Also,
considering the high costs and the need to administer
IGF1 subcutaneously, this approach deserves further
evidence from large RCTs before its efficacy can be
considered proven.
CONCLUSIONS
With very few exceptions, the current pharmacotherapy
of childhood neuropsychiatric disorders has been
directly derived from adult psychiatry. This poses major
problems when drugs and dosages prescribed for schizo-
phrenia or bipolar disorder are applied to patients with
ASD, given their greater sensitivity to psychoactive
drugs and the lower doses required. Also, adverse events
and paradoxical effects tend to be more frequent com-
pared to neurotypical individuals suffering from other
psychiatric or behavioral disorders. Sensory issues and
motor coordination deficits must also be taken into
account in prescribing psychoactive drugs: liquid forms
may be mandatory in small children with major swallow-
ing deficits but pills may be easier to administer to ASD
children with strong olfactory hypersensitivity or highly
fixed visuo/olfactory sensory rituals. Finally, the state-
ment “once you have seen one autistic child, you have
seen one autistic child” is apt in reference to psychophar-
macologic therapy. Interindividual variability in drug
response and tolerability is huge and the psychopharma-
cology of ASD requires highly individualized psycho-
pharmacologic tailoring to fit each single patient. No
disorder can be more distant from a therapeutic “copy-
and-paste” approach than ASD.
405
In the past, the clinical benefits of psychotropic drugs
were often discovered accidentally and the mechanism
responsible for these improvements was studied post
hoc. At present, psychopharmacology is increasingly
based on knowledge of the molecular pathophysiology
underlying the behavioral disorder, using animal and cel-
lular models. This is especially evident in monogenic
syndromic forms of autism, although the greater com-
plexity of the human brain at times prevents the success-
ful outcomes observed in animal models to be paralleled
by similar clinical outcomes in autistic patients. The
experimental use of neurons obtained from human
induced pluripotent stem cells (iPSC) represents the cur-
rent frontier of the individualized functional characteri-
zation and in vitro identification of the drugs that
might be most effective in reverting the negative conse-
quences of a genetic mutation or chromosomal anomaly,
analyzed in the context of the whole genome of the
patient (Kathuria et al., 2017). Targeted psychopharma-
cology has now reached the stage of large phase III trials,
and studies are underway with many promising com-
pounds. Meanwhile, the careful use of currently avail-
able psychoactive drugs, though not directly effective
upon core autistic symptoms, can ameliorate problem
behaviors, sleep disturbances, and comorbid disorders,
facilitating integration in school and work environments,
enhancing the efficacy of behavioral intervention, and
improving significantly the quality of life of patients
and their families. This, in and of itself, is a clinical target
very much worth pursuing.
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