Pharmacology & Therapeutics 230 (2022) 107939

Contents lists available at ScienceDirect

Pharmacology & Therapeutics

journal homepage: www.elsevier.com/locate/pharmthera

Novel treatments for autism spectrum disorder based on genomics

and systems biology
Danielle Baribeau a, Evdokia Anagnostou b,⁎
a
Department of Psychiatry, University of Toronto, Canada
b
Department of Pediatrics, University of Toronto, Holland Bloorview Kids Rehabilitation Hospital, Toronto, ON, Canada

a r t i c l e i n f o a b s t r a c t

Available online 24 June 2021 Background: Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder with a
complex underlying genetic architecture. There are currently no known pharmacologic treatments for the core
ASD symptoms of social deficits and restricted/ repetitive behavior. However, there are dozens of clinical trials
Editor: S. J. Enna currently underway that are testing the impact of novel and existing agents on core and associated symptoms
in ASD.
Keywords: Methods: We present a narrative synthesis of the historical and contemporary challenges to drug discovery in
Autistic disorder ASD. We then provide an overview of novel treatments currently under investigation from a genomics and sys-
Drug therapy tems biology perspective.
Clinical trials
Results: Data driven network and cluster analyses suggest alterations in transcriptional regulation, chromatin re-
modelling, synaptic transmission, neuropeptide signalling, and/or immunological mechanisms may contribute to
or underlie the development of ASD. Agents and upcoming trials targeting each of the above listed systems are
reviewed.
Conclusion: Identifying effective pharmacologic treatments for the core and associated symptom domains in ASD
will require further collaboration and innovation in the areas of outcome measurement, biomarker research, and
genomics, as well as systematic efforts to identify and treat subgroups of individuals with ASD who may be dif-
ferentially responsive to specific treatments.
© 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2. Challenges for drug discovery in ASD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
3. Emerging biological models and novel pharmacologic treatments in ASD . . . . . . . . . . . . . . . . . . . . 6
4. Future considerations and next steps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Declaration of competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Abbreviations: 22q11DS, 22q11.2 deletion syndrome; ABC, Aberrant Behavior Checklist; ADHD, Attention-deficit/hyperactivity disorder; ADOS, Autism Diagnostic Observation
Schedule; AIM, Autism Impact Measure; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; ASD, Autism spectrum disorder; AVPR1a, Arginine vasopressin receptor 1a;
CARS, Childhood autism rating scale; CGI, Clinical Global Impression Scale; CNV, Copy number variant; cAMP, cyclic AMP; DNA, Deoxyribonucleic acid; EEG, electroencephalogram; E:I,
Excitatory to inhibitory signalling ratio; FDA, Food and Drug Administration; FXS, Fragile X syndrome; GABA, Gamma aminobutyric acid; GSK-3, glycogen synthase 3; HDAC, histone
deacetylase; IGF-1, Insulin-like growth factor 1; MAPK, Mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; mGluR, metabotropic glutamate receptor; NAC, N-ace-
tyl-cysteine (NAC); NF1, Neurofibromatosis type 1; NMDA, N-Methyl-D-aspartate; PDE4D, phosphodiesterase-4D; PTEN, Phosphatase and tensin homolog; RCT, randomized controlled
trial; RNA, Ribonucleic acid; SNP, Single nucleotide polymorphism (1); SNV, Single nucleotide variant; SRS, Social Responsiveness Scale; TSC, Tuberous sclerosis complex; VABS,
Vineland Adaptive Behavior Scale.
⁎ Corresponding author at: Autism Research Centre, Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, 150 Kilgour Road, Toronto, ON M4G 1R8, Canada.
E-mail address: [email protected] (E. Anagnostou).

https://doi.org/10.1016/j.pharmthera.2021.107939
0163-7258/© 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
D. Baribeau and E. Anagnostou Pharmacology & Therapeutics 230 (2022) 107939

1. Introduction Box 1:

Autism spectrum disorder (ASD) is a neurodevelopmental disorder

Key Points:
that is usually identified in early childhood. Initial descriptions of the
condition emerged in the 1960s (Kanner, 1968). Current prevalence es- 1) There are currently no pharmacologic agents that treat re-
timates now suggest that 1–3% of children are affected (Christensen stricted/repetitive behavior or social deficits in ASD.
et al., 2019). The core symptoms of ASD are social communication defi- 2) Many agents with novel psychopharmacologic mechanisms
cits, and restricted/ repetitive patterns of behavior (American Psychiat- and/or molecular targets, in mostly early-stage trials, show
ric Association, 2013). Characteristically, children with autism present promise.
with early delays in social skills (e.g., not making friends, decreased or 3) Novel approaches in trial design, outcome measurement
unusual eye contact), often accompanied by delayed or absent creative and genomics will facilitate drug discovery in ASD.
play skills, delayed or unusual patterns of speech, repetitive behavior
such as rocking/ flapping movements, and/or highly intense interests
in a restricted range of topics (e.g., subway trains, elevator cars, calen-
dars). Although threshold severity levels of the core symptom domains 2. Challenges for drug discovery in ASD
are required for an ASD diagnosis, the condition is also associated with a
variety of other symptoms across developmental, cognitive, and psychi- 2.1. ASD is a clinically heterogeneous condition
atric domains (discussed further below).
Despite the relatively high prevalence of this condition, there are ASD is a highly heterogeneous condition with respect to the core
presently no approved (or effective off-label) pharmacologic treat- symptoms, regarding associated features and comorbid disorders, and
ments for the core symptom domains. Two atypical antipsychotics even over time within the same individual. Regarding core symptoms,
(risperidone and aripiprazole), which act on the D2 dopamine recep- autism presents along a wide spectrum of severity and abilities; symp-
tor, have received Food and Drug Administration (FDA) approval for toms range from subtle social difficulties without intellectual disability
use to reduce irritability/ aggressive behavior in the context of ASD (previously called ‘high functioning autism’ or Asperger syndrome), to
(Owen et al., 2009; RUPP, et al., 2002). There have been numerous, a severe and pervasive condition with self-injurious behavior, intellec-
mostly early stage, clinical trials in ASD using neuropeptide, neuro- tual disability and minimal to no verbal communication.
transmitter, glutamatergic or other nervous systems acting agents, Furthermore, individuals with autism experience significantly
either alone, or paired with a psychosocial intervention. So far, higher rates of a number of additional developmental, psychiatric and
most trials have not found significant differences on their primary also medical comorbidities. Most common are intellectual disability
endpoint, have been underpowered, or have not been reproducible. (10–50%), seizure disorders (10–20%), mental health or learning disor-
Unlike the dopamine hypothesis in psychosis/ADHD, or the seroto- ders (e.g., ADHD, anxiety) (10–50%), and gastrointestinal problems (ap-
nin hypothesis in depression, a single modifiable biological model proximately 50%) (Lai et al., 2019; Lukmanji et al., 2019; McElhanon,
for social impairment and/or repetitive behavior in ASD has McCracken, Karpen, & Sharp, 2014; Rydzewska et al., 2019). ASD is
remained elusive. Overall, current evidence-based interventions for also associated with increased rates of congenital malformations
core symptoms remain psychosocial or behavioral in nature (Ameis (Sigmon, Kelleman, Susi, Nylund, & Oster, 2019), hearing and vision
et al., 2018). Numerous challenges have arisen with respect to drug loss, and physical disabilities (Rydzewska et al., 2019), among other
development in ASD, including substantial heterogeneity in the clin- physical health conditions. In this setting, ASD can be conceptualized
ical presentation, symptom overlap with other psychiatric and de- as neurodevelopmental disorder with potential effects across multiple
velopmental disorders, uncertainty and heterogeneity regarding organ systems.
etiology and neurobiology, with differential environmental and ge- This clinical heterogeneity is in line with an emerging theory that
netic causes implicated, and a lack of consensus regarding the valid- there is no single ‘autism;’ instead, many argue that autism spectrum
ity of study endpoints. disorder(s) should be conceptualized as a cluster of distinct biological
Recently, research efforts have shifted towards understanding the conditions arising from different etiological mechanisms, with some
substantial heterogeneity in ASD, in hopes of identifying clinically similar clinical/behavioral downstream phenotypes (Geschwind &
meaningful subtypes or clusters. Chromosomal microarray analysis is Levitt, 2007; Happé, Ronald, & Plomin, 2006; Lombardo, Lai, & Baron-
now standard of care for those with developmental disorders including Cohen, 2019). Other models propose that reducing the clinical and mo-
ASD (Shen, et al., 2010). Genetic technologies with increasing resolution lecular heterogeneity of ASD into smaller categories could be helpful to
are becoming more accessible in both research and clinical settings guide the diagnostic work-up, and to further refine research cohorts.
(Tammimies et al., 2015; Yuen et al., 2015). Genomic data combined Specifically, individuals with autism can be clinically classified into
with a systems biology approach are beginning to elucidate the genetic those with associated morphological features (e.g., facial differences,
architecture underlying neurodevelopmental disorders, and potentially congenital malformations)- termed ‘complex autism’; and those
identify novel therapeutic targets. Systems biology (as opposed to tradi- without- termed ‘essential autism’ (Fernandez & Scherer, 2017). Simi-
tional, more reductionistic biology), applies computational modelling larly, results of genetic testing may identify no underlying explanation
and computer science methods to large datasets across different units (i.e., ‘idiopathic ASD’), may confirm classic ASD-associated syndromes
of analysis (genomics, proteomics, imaging, etc.), and biological systems (e.g., Fragile X syndrome- FXS), or may identify emerging ASD-risk var-
(e.g., immune, cell signalling, metabolism) to try to understand the en- iants (e.g., NRXN1 deletions) (Fernandez & Scherer, 2017; Weiner et al.,
tire picture with respect of a biological or pathological process 2017). In this setting, biological treatment strategies presuppose that
(Kirschner, 2005). In this setting, the present review will summarize there are either a) shared final common pathways towards social im-
the historical challenges to drug discovery in ASD, review recent and pairment/ repetitive behavior which are biologically modifiable across
emerging theories with respect to etiopathogenesis with a focus on ge- the spectrum irrespective of underlying etiology, or b) smaller sub-
nomics, and survey emerging pharmacologic agents for ASD currently in groups with common mechanisms or pathways for which specific treat-
clinical trials from a systems biology perspective (see Box 1). In order to ments may be effective. Irrespective of how it is conceptualized, the
support efficient clinical translation into novel therapeutics, potential substantial clinical heterogeneity presents a challenge for drug discov-
next steps for the field are discussed. ery with respect to the identification of meaningful treatment targets,

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D. Baribeau and E. Anagnostou Pharmacology & Therapeutics 230 (2022) 107939

recruitment of homogeneous populations, and for outcome approximately ten years (Miller et al., 2010). Whole genome and
measurement. whole exome sequencing may further increase the diagnostic yield;
exome sequencing has been recommended as a first-tier diagnostic
2.2. Indistinct diagnostic boundaries with other psychiatric and develop- test as well (Clark et al., 2018; Srivastava, et al., 2019; Tammimies
mental disorders et al., 2015). In this setting, efforts to curate specific lists of established
and novel ASD variants/ genes are underway (Schaaf et al., 2020;
Further to the clinical heterogeneity within ASD samples, the core Vorstman et al., 2017), with over 1000 ASD-associated genes, and over
symptoms and associated features have also been found to substantially 2000 ASD associated CNVs currently identified (Yuen et al., 2017;
overlap with other psychiatric and developmental disorders. For Pereanu et al., 2017). Each genetic cause or variant is individually rare
example, children with ADHD commonly experience deficits in the within ASD samples, typically affecting 1% or less of those with ASD.
social domain, and hyperactive/impulsive symptoms affect a sub- Most CNVs associated with ASD are not phenotypically specific, they
stantial proportion of children with ASD (Krakowski et al., 2020). also dramatically increase the risk for other psychiatric disorders
Rates of comorbidity between two conditions are approximately 20% (Chawner et al., 2019). The majority of CNVs and SNVs in ASD arise de
(Hollingdale, Woodhouse, Young, Fridman, & Mandy, 2019; Lai et al., novo (i.e., are not inherited from either parent but instead occur during
2019). Similarly, there is clinical overlap and high rates of comorbidity embryogenesis), although a minority are inherited. Common genetic
with anxiety disorders (van Steensel, Bogels, & Perrin, 2011), and variation (essentially one's inherited genetic background comprised of
obsessive-compulsive disorder (Kim, Reynolds, & Alfano, 2012; Zandt, single nucleotide polymorphisms- SNPs) may also contribute to ASD
Prior, & Kyrios, 2007). Family members of individuals with ASD have risk in up to 25% of cases, or may act synergistically with rare variants
been shown to have higher rates of ASD traits without meeting criteria to shape their expression (Niemi et al., 2018; Weiner et al., 2017).
for an ASD diagnosis (termed the ‘broader autism phenotype’) Taken together, the complex genetic architecture, extensive gene and
(Sucksmith, Roth, & Hoekstra, 2011). Data from large scale observa- variant lists, and the multifactorial etiologies underlying ASD risk have
tional studies recruiting from across multiple psychiatric disorders sug- so far obscured the identification of specific molecular targets or pro-
gest that the same common genetic risk factors may underlie multiple cesses for biological manipulation.
psychiatric conditions including ASD (Lee et al., 2013). Overall, recent
research trends and data support a move towards a dimensional look 2.4. Most CNVs and SNVs associated with ASD are pleiotropic, variably
at psychopathology, and away from the categorical ‘disorder-based’ ori- expressed, and incompletely penetrant
entation that currently dominates the clinical field (Insel et al., 2010).
For therapeutic trial design, however, categorical ‘disorder-based’ inclu- In depth research into specific CNVs and single gene disorders asso-
sion criteria are currently required for subsequent medication approval ciated with ASD has revealed further complexity, given their pleiotropic
by regulatory agencies. Symptom severity thresholds in ASD trials also effects, variable expression, incomplete penetrance, and lack of behav-
require nuanced consideration given previous data suggesting that ioral specificity.
1) those with higher levels of symptomatology may be more likely to Pleiotropy occurs when the same genetic mutation has multiple un-
separate from placebo for psychiatric symptoms (Fournier et al., related downstream effects across different organ systems. FXS for ex-
2010), or for repetitive behavior (King et al., 2013); while 2) social im- ample, is a single gene disorder associated with developmental delay/
pairment in ASD may reflect a skill deficit where those with higher base- ASD and also macro-orchidism, hypotonia, tremor/ataxia and character-
line functioning/ abilities may be more likely to respond to therapy (or istic facial features. Variable expression is when the same genetic muta-
be captured on existing outcome measures) (Veenstra-VanderWeele tion or variant leads to diverse phenotypes in different individuals
et al., 2017). (e.g., ASD vs. schizophrenia, vs. congenital heart disease); incomplete
penetrance is a related concept where the same specific variant or
2.3. Multifactorial etiology and genetic heterogeneity mutation can lead a range of severity in expression, from no or subclin-
ical symptoms to severe symptoms in different carriers. 22q11.2 dele-
Investigations into the etiopathogenesis of ASD suggest a number of tion syndrome (22q11DS), for example is a well characterized CNV
environmental, metabolic, immune and genetic mechanisms or risk fac- known to occur in 1 in 1000 pregnancies. Despite having the same dele-
tors may be at play, with differential, additive and potentially synergis- tion breakpoints affecting approximately 90 genes, individuals with
tic effects in each individual case (Kim et al., 2019). On meta-analysis, 22q11DS variably experience childhood immunodeficiency (~75% of pa-
several prenatal and neonatal environmental factors including ad- tients), congenital cardiac anomalies (~75%), hypocalcaemia (~50%),
vanced parental age, prenatal valproic acid exposure, gestational diabe- palatal abnormalities (~75%), language and developmental delays
tes, neonatal hypoxia, maternal obesity, and prematurity, for example, (~70%), schizophrenia (~25%), autism (18%) and other psychiatric and
have statistical associations with an ASD diagnosis, each individually developmental disorders including intellectual disability, attention-
with a low effect size or wide confidence interval around the estimate deficit/hyperactivity disorder (ADHD), and anxiety (Fung et al., 2015;
(Jiang et al., 2016; Lord et al., 2020; Modabbernia, Velthorst, & McDonald-McGinn et al., 2015; Schneider, et al., 2014).
Reichenberg, 2017). International collaborations are underway to systematically identify,
Advances in genomics research in particular have revealed that for a characterize and define the impacts of rare genetic variants on develop-
substantive minority of cases of ASD (approximately 10–30%), an un- ment and mental health (e.g., www.22q11-ibbc.org/, research.mss.ng)
derlying pathogenic or likely pathogenic genetic variant can now be which may help delineate mechanisms underlying developmental dis-
identified (Miller et al., 2010; Tammimies et al., 2015). These include orders more broadly. However, with respect to drug discovery in ASD,
1) historically recognized genetic syndromes [e.g., FXS, Tuberous sclero- genetic heterogeneity within the ASD spectrum and variable expression
sis complex (TSC), Rett syndrome, neurofibromatosis (NF1), etc.]; of individual variants, creates a challenge for homogeneous population
2) more recently identified copy number variants (CNVs, i.e., deletion recruitment, sample size attainment, and biological target identifica-
or duplication of approximately 2000–10,000 base pairs, for example tion. Even for single gene disorders, such as FXS, where specific molec-
16p11.2 duplications); 3) single nucleotide variants (SNVs, where a ular mechanisms and targets (e.g., decreased mGluR5 inhibition) have
change of a single base pair affects the expression of a single gene); been delineated and showed clinical efficacy in animal models (Berry-
and 4) tandem DNA repeat expansions (e.g., sections of DNA that be- Kravis et al., 2018; Michalon et al., 2012), multiple human trials have
come pathologically repeated/ expanded during replication) (Trost not found clear evidence of benefit (Berry-Kravis et al., 2018). Some
et al., 2020). Genetic investigations including chromosomal microarray trialists have opted to recruit individuals with specific genetic syn-
analysis have been considered a routine diagnostic test for ASD for dromes and comorbid ASD (e.g., ASD in NF1; Table 1) to optimize

3
 Table 1
Novel pharmacologic trials underway in ASD as registered on NCT.gov.

Population Molecular Target or Mechanism Drug (duration of threatment) Primary Outcome Trial number

Transcriptional Regulators
Autism (5–12 years) Insulin Like Growth Factor Receptor (IGF1R) agonism activates PI3K/AKT/mTOR IGF-1 (12 weeks) Social withdrawal (ABC-SW) NCT01970345
and MAPK/ERK pathways
Phelan McDermid (5–12 Insulin Like Growth Factor Receptor (IGF1R) agonism activates PI3K/AKT/mTOR IGF-1 (12 weeks) Social withdrawal (ABC-SW) NCT01525901
years) and MAPK/ERK pathways
D. Baribeau and E. Anagnostou

PTEN (5–45 years) Inhibition of mTOR pathways by blocking the formation of the mTORC1 complex Everolimus (6 months) Tolerability and neurocognition NCT02991807
ASD in NF1 (16–65 Reduction in signalling via the Ras pathway by decreasing MAPK/ERK1/2 Lovastatin (3 days) MRS, TMS and EEG markers NCT03826940
years) phosphorylation

Chromatin Remodelling
ASD (13–30 years) Antioxidant effects including inhibition of cytochrome p450 enzymes, and Sulforaphane (22 weeks) Aberrant behavior (ABC), social responsiveness NCT02677051
reduction of HDAC activity (SRS) and global impression (CGI)
ASD (5–12 years) Contribution to DNA methylation Leucovorin/ Folinic acid (12 weeks) Language skills (CELF) NCT02839915
ASD (age 2.5–5 years) Contribution to DNA methylation Leucovorin/ Folinic acid (24 weeks) Social skills (Brief observation of social NCT04060030
communication change)

Synapse
ASD (5–17 years) GABAB agonist Arbaclofen (16 weeks) Social function (VABS) NCT03682978
16p11.2 deletion (5–17 GABAB agonist Arbaclofen (12 weeks) Articulation (GFTA-3) NCT04271332
years)
ASD (5–17 years) GABAB agonist Arbaclofen (16 weeks) Social function (VABS) NCT03887676
ASD and controls GABAA positive allosteric modulator AZD7325 (single dose) Neuroimaging and electrophysiology outcomes NCT03678129
(18–60 years)
FXS (18–50 years) GABAA positive allosteric modulator AZD7325 (12 weeks) Amyloid precursor protein levels NCT03140813
ASD (15–45 years) GABAA modulator RO7017773 (12-week) Adaptive behavior (VABS composite) NCT04299464
ASD (16 years and up) NMDA antagonist Memantine (12 weeks) CGI-improvement NCT02811627

4
ASD (8–18 years) NMDA antagonist Memantine (12 weeks) CGI-improvement NCT03553875
ASD and related deficits NMDA antagonist Memantine (12 weeks) CGI-improvement NCT03553875
(8–18 years)
ASD (2–15 years) NMDA antagonist Ketamine +/− dexmedetomidine (12 weeks) Core ASD symptoms (ADOS and ADI-R) NCT03434366
ASD (2–7 years) Diuretic, effects GABA indirectly via chloride Bumetanide (6 months) ASD symptoms (CARS) NCT03715153
ASD (7–18 years) Diuretic, effects GABA indirectly via chloride Bumetanide (6 months) ASD symptoms (CARS) NCT03715166
ASD (3–12 years) Glutamate modulator and antioxidant NAC (single dose) Glutamate metabolites and gamma synchronization NCT04278898
on neuroimaging/ EEG

Neuropeptide
ASD (ages 5–9 years) Oxytocin receptor agonism Oxytocin paired with pivotal response training (16 Social responsiveness NCT03370510
weeks) (SRS)
ASD (8-11 years) Oxytocin receptor agonism Oxytocin plus social skills group (12 weeks) Social behavior (composite across several scales) NCT02918864
Phelan-McDermid (age Oxytocin receptor agonism Oxytocin (12 weeks) Social withdrawal (ABC) NCT02710084
5–17 years)
ASD (5–40 years) Oxytocin receptor agonism Oxytocin (single dose) Social cognition (RMET/ DANVA/ Lets Face IT!) NCT02493426
ASD (12–55 years) Oxytocin receptor agonism Oxytocin Social responsiveness (SRS) NCT02985749
(8 weeks)
ASD (18–54 years) Oxytocin receptor agonism TTA-121 (Novel oxytocin nasal spray) (4 weeks) Core ASD symptoms (ADOS) (social reciprocity NCT03466671
score)
ASD (6–17 years) Arginine vasopressin receptor agonism Vasopressin nasal spray (8 weeks) Social responsiveness (SRS) NCT03204786

Immune
ASD (14–25 years) Precursor to most steroid hormones; some indirect neural activity on numerous Pregnenolone (steroid) (14 weeks) Irritability (ABC) NCT02627508
neurotransmitters (Schumacher et al., 2008)
ASD (18–30 years) Monoclonal Antibody against IgE Omalizumab (24 weeks) ASD symptoms (SRS, ABC and other measures) NCT04535817
ASD (12–22 years) Reduction in bacterial colonization Minocycline (antibiotic) (4 weeks) Safety and aberrant behavior (ABC) NCT04031755
ASD (30 months – 7 Gut dysbiosis Lactobacillus plantarum (16 weeks) ASD and ADHD symptoms (CBCL and ADHDT) NCT03982290
years)
ASD (7–20 years) Gut dysbiosis Fecal microbiota transplant (6 weeks) Safety and GI symptoms (ASD symptoms secondary NCT04246398
endpoint on SRS)
Pharmacology & Therapeutics 230 (2022) 107939
D. Baribeau and E. Anagnostou Pharmacology & Therapeutics 230 (2022) 107939

ABC-SW: aberrant behavior checklist- social withdrawal subscale; ADHDT: Attention-deficit/hyperactivity disorder test; ADI-R: autism diagnostic interview-revised; ADOS: autism diagnostic observation schedule; ATEC: autism treatment evaluation
Search of clinicaltrials.gov database in October 2020, for randomized controlled medication trials that are ‘not yet recruiting, recruiting, or active not recruiting, for autism spectrum disorder. Identified agents were subsequently searched as keywords
to screen for trials in specific genetic syndromes. Not included in the table are trials of existing psychotropic medications in ASD (e.g., stimulants), trials of fetal cord blood or stem cell transplant, and a few select agents which did not fit into the above

checklist; CARS: clinical autism rating scale; CBCL: child behavior checklist; CELF: clinical evaluation of language fundamentals; CGI: clinical global impression scale; DANVA: diagnostic analysis of nonverbal accuracy; EEG: electroencephalogram;
GFTA: Goldman Fristoe test of articulation; HDAC: Histone deacetylase; MRS: magnetic resonance spectroscopy; PDDBI: pervasive developmental disorder behavior inventory; RBS-R: repetitive behavior scale-revised; RMET: reading the mind in the
genetic homogeneity. Others have chosen to examine the spectra of ASD
NCT03408886
NCT04182633
NCT03369431
NCT03426826
NCT03514784
NCT04293783

NCT03829878

NCT04312932
traits within a genetic subtype irrespective of ASD diagnosis (e.g., social
abilities within Phelan McDermid syndrome; Table 1). As discussed fur-
ther below, emerging efforts to parcellate or stratify genetic variants
into final common pathways or characterize genetic subtypes of ASD
is hoped to yield biologically distinct clusters more amenable to
targeted therapeutics.
ASD symptoms (ADOS); salivary microbiota
ASD symptoms (CARS) and GI symptoms

2.5. Limitations in outcome measures, biomarkers and endpoints

Safety; Repetitive Behavior (RBS-R)

Our ability to evaluate the effectiveness of treatments depends on

the quality and validity of the outcome measures and trial endpoints
chosen (Clark & Watson, 1995; Kirshner & Guyatt, 1985). Unfortunately,
ASD Symptoms (CARS-2)

ASD symptoms (PDDBI)

ASD symptoms (CARS)

ASD symptoms (ATEC)

there is a lack of consensus with respect to outcome measurement in

ASD. Specifically, what constitutes an important change in symptoms
categories [i.e., a digestive enzyme therapy (CM-AT); JNJ-42165279 (fatty acid hydroxylase inhibitor related to endocannabinoid metabolism), and a proton pump inhibitor (esomeprazole)].

or behavior may vary highly between individuals across the autism

spectrum and lifespan and depend greatly on baseline cognitive abili-
ties; these changes may not be captured on classic survey scales relying
Safety

on caregiver or self-report, or may be obscured by other items. Similar

to self-report measures in other mental health conditions, trials in
Microbiota Transplant Therapy (up to 22.5 months)

Long chain polyunsaturated fatty acid (Omega 3–6)

ASD have shown moderate placebo responses (effect size = 0.45) on

caregiver reports (Masi, Lampit, Glozier, Hickie, & Guastella, 2015). Par-
Multistrain probiotic (BB-12 + LGG) (84 days)

Oral Full-Spectrum Microbiota transplant (24

ents also tend to rate children as improved over time simply by partic-
Microbiota Transplant Therapy (14 weeks)

ipating in a therapeutic trial design, even without receiving any

Fecal microbiota transplant (24 weeks)

treatment (Jones, Carberry, Hamo, & Lord, 2017). Clinician ratings (for
example clinical global impression scores) may be even more suscepti-
Probiotic (Vivomixx) (24 weeks)

Probiotic- L.Reuteri (6 months)

ble to placebo effects than parents scales (Masi et al., 2015).

supplementation (90 days)

In 2011, Autism Speaks and the National Institute of Mental Health,

with industry and FDA support, organized a think tank to evaluate out-
come measures for clinical trials in ASD. Three manuscripts were pro-
duced, which suggested measures for social communication, repetitive
behaviors, and anxiety, respectively (Anagnostou et al., 2014;
Lecavalier et al., 2014; Scahill et al., 2015). All measures recommended
eyes test; SRS: social responsiveness scale; TMS: transcranial magnetic stimulation; VABS: vineland adaptive behavior scale.
weeks)

for use came with significant limitations. The vast majority of medica-
tion trials in ASD have selected multi-item symptom scales completed
by a parent/ caregiver or clinician as the primary endpoint (see exam-
ples described in (Baribeau & Anagnostou, 2014a, 2014b), and listed in
Table 1). For example, the FDA approved risperidone and aripiprazole
based on changes in scores on the Aberrant Behavior Checklist (ABC), ir-
ritability subscale (15 items from a parent report measure) (Aman,
Singh, Stewart, & Field, 1985). Recently, several trials have chosen to
use the social domain of the Vineland Adaptive Behavior Scale (VABS)
(Sparrow & Cicchetti, 1989), as their primary endpoint, given trial
data showing significant changes in this subscale as a secondary end-
point, and potentially less placebo response than other measures
(Berry-Kravis et al., 2012; Bolognani et al., 2019). The VABS is a semi-
structured clinician administered interview of caregivers about their
child's functioning/ abilities in everyday tasks; questions progress
from basic to more complex, and are standardized for age. Other trials
have used various subscales or total scores from screening/ diagnostic
measures in ASD (e.g., the Social Responsiveness Scale- SRS, or the Au-
Anti-inflammatory effects

tism Diagnostic Observation Schedule -ADOS) which can be problem-

atic for clinical trials as the objective is to measure change over time
(Scahill, 2015).
Gut dysbiosis
Gut dysbiosis
Gut dysbiosis
Gut dysbiosis
Gut dysbiosis
Gut dysbiosis

Gut dysbiosis

Some studies have attempted to identify more proximal and reliable

behavioral or biological markers of behavior change in ASD, including
performance on standardized mentalization tasks (e.g., recognizing fa-
cial expressions in pictures) (Baron-Cohen, Wheelwright, Hill, Raste, &
Plumb, 2001; Dal Monte et al., 2014), frequency or patterns of eye con-
tact from eye tracking software (Jones & Klin, 2013), changes in func-
ASD (18 months- 8
ASD (18–60 years)

tional or electrophysiological neuroimaging parameters (Grabb, Cross,

ASD (5–17 years)
ASD (3–16 years)
ASD (5–17 years)

ASD (5–17 years)

ASD (2–6 years)

Potter, & McCracken, 2016; Just, Cherkassky, Keller, Kana, & Minshew,
ASD (4–16)

2007; Kleinhans et al., 2011; Koshino et al., 2008; Liu et al., 2015), or bi-
years)

ological assays, for example (Stivaros et al., 2018). While significant dif-
ferences have been observed with such measures compared to control
populations, and in some early trials (Grabb et al., 2016; Stivaros et al.,

5
D. Baribeau and E. Anagnostou Pharmacology & Therapeutics 230 (2022) 107939

2018), validation of these endpoints with respect to change in meaning- 2.7. Summary
ful clinical outcomes is lacking. Thus, there are presently no surrogate
endpoints, or likewise, clinically relevant biomarkers (outside of a ge- ASD is a clinically and biologically heterogeneous condition; symp-
netic diagnosis) for treatment response in ASD [see a position paper toms and underlying genetic architecture also overlap substantially
and review (Beversdorf & Missouri Autism Summit, 2016)]. with other neuropsychiatric and developmental disorders. The wide
That said, given concerns with the validity, generalizability, and high spectrum of severity, variable medical and psychiatric comorbidity,
placebo response rates of many symptom surveys, a biomarker closer in and association with numerous rare genetic syndromes/variants creates
proximity to the underlying pathobiology may prove exceedingly help- additional challenges for outcome identification and measurement, and
ful for novel therapeutics. For example, a common hypothesis proposes for trial design and recruitment.
that an imbalance of excitatory-to-inhibitory (E:I) signalling contributes
to the etiopathogenesis of ASD (Sohal & Rubenstein, 2019). Data from 3. Emerging biological models and novel pharmacologic treatments
magnetic resonance spectroscopy (MRS) studies have found wide- in ASD
spread, although heterogeneous, disruptions in excitatory and inhibi-
tory signalling metabolites in ASD (Ajram et al., 2019; Ipser et al., 3.1. Data driven cluster analyses suggest common genetic pathways and
2012; Maria et al., 2021). In experimental settings, MRS has been used networks may underlie ASD
to measure the effects of specific drug challenges on E:I balance
in vivo [for a review see (Ajram et al., 2019)]. E:I balance in ASD has Given the challenges and heterogeneity described above, many in-
also be quantified using EEG (Bruining et al., 2020), and transcranial vestigators have recently moved towards data-driven approaches
magnetic stimulation (TMS) (Masuda et al., 2019). Animal and neuro- using clustering and network analyses in ASD. When applied to genetic
imaging research have begun to elucidate the specific neurocircuits data, the hope is that these methods can help identify biologically
that may be disrupted in ASD (Kelly et al., 2020); different ASD genetic (more) homogeneous subgroups or common pathways in ASD that
variants may cluster into different subtypes of aberrant functional con- could be amenable to pharmacotherapy (Fig. 1).
nectivity, for example (Zerbi et al., 2020). Experiments using functional For example, in 2010, in their landmark paper, Pinto et al. analyzed
MRI have also been able to quantify the effects of specific agents on con- microarray data from approximately 1000 individuals with autism com-
nectivity patterns following single dose challenges (Wichers et al., pared to controls (Pinto et al., 2010); there was a significantly higher
2021). Likewise, data-driven analyses of structural neuroimaging burden of rare CNVs in those with ASD. When variants were mapped
scans from human (Kushki et al., 2019), or genetic mouse models of to known gene sets (i.e., groups of genes known to be related by func-
ASD (Ellegood et al., 2015), may help to identify biologically or tion or molecular pathway), 76 gene sets (2% of all sets tested) were
behaviourally meaningful clusters reflective of distinct trajectories ame- found to be disproportionately affected by ASD-associated CNVs. Exam-
nable to specific targeted therapeutics. Overall, it is hoped that some of ples of specific pathways implicated included those involved in CNS de-
these emerging methods may be able to help capture agents with po- velopment, neuronal cell proliferation and migration, neuronal motility
tential therapeutic value, identify patients with specific treatment re- and axonal projection, kinase signalling pathways and transcriptional
sponsive ASD subtypes, or track treatment response. regulators (including MAPK, Ras and mTOR), the microtubule cytoskel-
eton, adhesion molecules, chromatin regulation and glycosylation. Fol-
low up studies using much larger datasets and sophisticated statistical
2.6. Optimal dose and timing of intervention methods, [e.g., (De Rubeis, et al., 2014; Pinto et al., 2014; Satterstrom,
et al., 2020)], have confirmed similar results.
An important additional consideration and challenge to drug discov- Overall, from the above-described data, genetic variants in autism
ery in ASD centers on the optimal timing of pharmacologic intervention. can be grouped into those that affect 1) transcriptional regulators
ASD is a lifelong neurodevelopmental disorder with biological differ- and kinase associated cell signalling pathways (e.g., mTOR, Ras, MAPK,
ences emerging very early in life (Bonnet-Brilhault et al., 2018; Wnt), 2) chromatin remodelling and epigenetic processes (important
Satterstrom, et al., 2020). Large scale studies examining ASD- for neurogenesis and connectivity), or 3) synapse function (including
associated risk genes have shown that many are prenatally expressed ion channels, receptors, scaffolding proteins and cytoskeleton) (Fig. 2).
(Satterstrom, et al., 2020). At the same time, the same genetic variant These findings align with the rationale for some emerging pharmaco-
or biological process may play different roles in brain development logic trials in ASD, and can be helpful to group existing and novel treat-
and pathology across the lifespan, so the biological target and/or role ments with respect to mechanisms of action (Fig. 1). Novel/ emerging
for psychopharmacology may actually be changing with age. For exam- agents are reviewed below by group; we emphasize that none are cur-
ple, 22q11DS is associated with increased risk of early childhood lan- rently approved nor indicated for treatment of core ASD symptoms. Fur-
guage, social, attentional and developmental delays, followed by ther data, traditionally two or more phase-3 randomized controlled
adolescent onset mood, anxiety and psychotic disorders, and subse- trials showing both efficacy and tolerability, are required before these
quently an increased risk for early onset for Parkinson's disease treatments may be recommended for clinical use. Where data are suffi-
(Butcher et al., 2013), each which may benefit from different medica- cient, agents with primary outcomes that are summarily negative,
tion strategies despite the same underlying genetic lesion. At the same equivocal, or suggestive of benefit will be highlighted.
time, in FXS, pharmacologic treatments targeting the underlying biol-
ogy in animal models do appear to have the potential to reduce neuro- 3.2. Pharmacological agents targeting transcriptional regulation
pathology even when applied in adulthood (Pop et al., 2012). Therefore,
in addition to identifying biologically effective medications, trials are Manipulation of transcriptional regulators such as Ras, mTOR and
needed to determine the optimal timing of intervention; a medication MAPK has been a focus of recent trials in ASD. The Ras-mitogen-acti-
trial that fails to show clinical benefit in adult populations still may vated protein kinase (Ras-MAPK) signalling pathway and the phos-
merit additional investigation in younger participants. Two recent ran- phatidylinositol 3-kinase–AKT–mammalian target of rapamycin (PI3K-
domized controlled trials of Bumetanide (see sections below) reported AKT-mTOR) signalling pathway play important roles in the regulation
clinical improvements in ASD symptoms in preschool-aged (3–6 of both the transcription and translation of proteins (Fig. 2). Initially rec-
years) (Zhang et al., 2020), but not school-aged (7–15 years) ognized to be a core process leading to cancer cell growth, these path-
(Sprengers et al., 2021), samples, although other design and analysis ways are now understood to be fundamental to synaptic plasticity and
factors, including challenges with effective blinding of treatment assign- CNS development. [For a review of the cellular biology see (Franz &
ment, may also have contributed to differences. Weiss, 2012), and for a review of these pathways in intellectual

6
D. Baribeau and E. Anagnostou Pharmacology & Therapeutics 230 (2022) 107939

Fig. 1.. Created with BioRender.com

disability/ development see (Borrie, Brems, Legius, & Bagni, 2017)]. In neuronal maintenance. Data from a recent paper identified tandem re-
addition to genetic clustering analyses, several chromosomal disorders peats in IGF-1 more commonly in individuals with ASD than their unaf-
and CNVs associated with ASD (e.g., FXS, NF1, TSC, Rett syndrome, fected siblings (Trost et al., 2020). In vitro studies using cells from
Phelan-McDermid syndrome) have been traced to mutations affecting patients with Phelan-McDermid syndrome (a CNV at 22q13.3 resulting
these pathways. This work is further supported by data showing that in deletion of the SHANK3 gene, and associated with autism in approxi-
the degree of overactivity in specific mTOR and MAPK proteins corre- mately 75% of cases) suggested that cells were deficient in excitatory
lated with severity of ASD symptoms in a small clinical cohort of idio- neurotransmission, which was corrected through treatment with IGF-
pathic autism (Rosina et al., 2019). Several recently identified ASD-risk 1 (Shcheglovitov et al., 2013). SHANK3 is a post-synaptic density protein
genes also appear to exert their developmental effects by impairing that connects synaptic receptors to downstream pathways. A pilot
transcriptional regulation pathways [for example SYNGAP1 and Ras cross-over study including nine children with Phelan-McDermid syn-
(Berryer et al., 2013)] (Fig. 2). drome found that treatment with IGF-1 was well tolerated and associ-
In terms of pharmacotherapy, insulin-like growth factor 1 (IGF-1), ated with improvement in repetitive behavior and irritability
is a growth factor important for brain development. It acts on the IGF-1 (Kolevzon et al., 2014). A randomized controlled trial using intranasal
receptor to trigger signalling via MAPK and mTOR pathways, ultimately insulin (which has some cross-reactivity at the IGF-receptor) in 25 chil-
affecting the transcription of proteins important for synaptogenesis and dren with Phelan-McDermid syndrome found non-significant benefits

7
D. Baribeau and E. Anagnostou Pharmacology & Therapeutics 230 (2022) 107939

Fig. 2. Note: This figure is for illustrative purposes; select pathways, agents, genes and biological processes have been simplified and merged together into a single diagram. The IGF-1
receptor was chosen to illustrate the Ras-MAPK and the AKT-mTOR pathways, however many other cell surface receptors also exert effects through this path. Histone deacetylase
(HDAC) inhibitors include novel agents (e.g., AR-42), valproic acid, and ketone bodies. Folate derivatives include folinic acid and leucovorin. NMDA modulators include memantine, ke-
tamine, and riluzole, amantadine, and D-cycloserine. This figure was created with BioRender.com.

8
D. Baribeau and E. Anagnostou Pharmacology & Therapeutics 230 (2022) 107939

in development, adaptive and social skills. In a mouse model of Rett syn- attachment to the inner cell surface (Fig. 2). Lovastatin treatment led
drome (MECP2 knock-out), endogenous IGF-1 levels were reduced; to benefits in the behavioral profile of NF1 mouse models (Li et al.,
treatment with IGF-1 recovered aspects of the behavioral and physio- 2005), but results of an RCT showed no benefits in attention or cognition
logical profile (Castro et al., 2014). Early descriptions in Rett syndrome in humans, despite no increase in reported adverse effects (Payne et al.,
in humans suggested recombinant IGF-1 was helpful for some associ- 2016). In FXS, mouse models suggested lovastatin corrected abnormal
ated symptoms including anxiety (Khwaja et al., 2014; Pini et al., protein synthesis and prevented seizures (Osterweil et al., 2013); lova-
2016), however a follow-up phase 1 RCT found symptoms of depres- statin treatment in a small pilot study improved scores on the aberrant
sion, hyperventilation and overall severity actually worsened in the behavior checklist for the majority of participants, with good tolerability
treatment arm, although some secondary analyses suggested possible (Çaku, Pellerin, Bouvier, Riou, & Corbin, 2014). A follow up randomized
benefits for repetitive behavior and social communication (O'Leary controlled trial recently found that lovastatin and placebo groups im-
et al., 2018). Interestingly, knock-out of the IGF-1 receptor restored as- proved comparably across all primary and secondary language and be-
pects of the behavioral phenotype in a mouse model of FXS (Wise, havioral measures in FXS, however (Thurman et al., 2020). Two out of
2017). Thus far, human data are too preliminary to make conclusions thirty participants in this trial discontinued early due to increased irrita-
about the effectiveness of this agent. Recent cellular data do support bility; otherwise, adverse effects did not differ between groups
possible heterogeneous treatment effects with potential responder (Thurman et al., 2020). An open label trial of lovastatin in Rett syndrome
and non-responder subgroups to IGF-1 in ASD (Linker, Mendes, & has recently completed as well (NCT02563860). Other trials of statins in
Marchetto, 2020). Two trials using IGF-1 in ASD are currently underway ASD are underway (Table 1). While outcomes from trials of statins in
(see Table 1). A recent study using a mouse of model autism suggested ASD appear negative so far, samples are small, and further study may
that manipulating the mTOR pathway with IGF-II may also be promising be merited.
(Steinmetz, Stern, Kohtz, Descalzi, & Alberini, 2018). In summary, agents targeting transcriptional regulation pathways in
Other work has targeted the mTOR pathway with chemotherapeutic ASD have the theoretical potential to ameliorate core symptoms in at
agents (e.g., rapamycin, everolimus) in neurodevelopmental disorders least some genetic subgroups. There are some very early efficacy signals
associated with mutations in proteins affecting the mTOR pathways for some agents (tideglusib, BPN14770); other agents require further
(e.g., TSC, NF1, PTEN) (Fig. 2). Benefits have been detected with respect study with attention to safety/tolerability concerns in particular
to skin manifestations in TSC (Krueger et al., 2013), and possibly sei- (e.g., IGF-1 modulators, mTOR modulators).
zures (Li et al., 2019; Mizuguchi et al., 2019). A small RCT showed no
benefits on primary or secondary outcomes with respect to cognitive
and ASD associated symptoms in TSC, however (Overwater et al., 3.3. Pharmacologic agents affecting chromatin remodelling and epigenetic
2019). In NF1, mTOR inhibitors are considered experimental with regulation
some data suggesting they reduced glioma (Ullrich et al., 2020), but
not plexifibroma size (Zehou et al., 2019); effects on neurocognitive Gene expression is also regulated through epigenetic processes in-
and behavioral profiles require further study (Table 1). Given the poten- volving chromatin, allowing the genome to change from ‘open’ to
tial toxicity of these agents, including high rates of stomatitis (Li et al., ‘closed’ positions and vice versa, for RNA transcription (Fig. 2). Muta-
2019), additional consideration of and data on the risk-to-benefit ratios tions affecting machinery regulating histone acetylation/methylation
are needed. (which trigger easily reversible changes in gene expression) or DNA
There are a series of other compounds under investigation that have methylation (causing long term changes in gene expression) can have
indirect effects on transcriptional regulation and/or other intracellular substantial effects on downstream development. A significant propor-
signalling pathways. For example, glycogen synthase 3 (GSK-3) is a con- tion of proposed ASD genes directly or indirectly affect chromatin re-
stitutionally active kinase that plays a large role in phosphorylating nu- modelling (De Rubeis, et al., 2014; Duffney et al., 2018). Variants
merous intracellular proteins, including those involved in wnt signalling affecting chromatin associated genes or methylation processes have
(important for neurotransmission- Fig. 2) (Beurel, Grieco, & Jope, 2015). been found to contribute to numerous specific rare disorders associated
GSK-3 inhibition is proposed to be one of the mechanisms by which lith- with ASD (e.g., Prader-Willi Syndrome, Angelman Syndrome, Coffin-
ium achieves mood stabilization in bipolar disorder, and this enzyme is sirus syndrome (ARID1B gene), Rett syndrome (MECP2) and Kleefstra-
also thought to contribute to the neuropathology of Alzheimer's disease syndrome (EHMT1) (Fahrner & Bjornsson, 2019). Mutations affecting
(King et al., 2014). Recently, tideglusib (a novel GSK-3 beta inhibitor) the gene for CHD8 (an epigenetic regulator that triggers transcriptional
showed trends towards improvement in social withdrawal and repeti- repression via chromatin remodelling) have shown strong associations
tive behavior, as well as significant improvements in adaptive function- with ASD (Bernier et al., 2014) (Fig. 2). Brain and blood methylation
ing and social abilities in a phase-2 RCT in ASD (Anagnostou, Bennett, profiles have been shown to vary between typically developing individ-
Thorpe, & Nicolson, 2018). With respect to tolerability, trials in adults uals and those with ASD for specific genomic regions/genes (Andrews
suggest diarrhea and a mild transaminitis may affect up to 10–30% of et al., 2018; Ellis, Gupta, Moes, West, & Arking, 2017; Ladd-Acosta
treated patients (del Ser et al., 2013; Tolosa et al., 2014). Another et al., 2014); the degree of methylation may also correlate with ASD
agent, BPN14770, is a novel negative allosteric modulator of symptom severity (Wong et al., 2014). Emerging data suggest that
phosphodiesterase-4D (PDE4D). PDE4D is a molecule important to intronic variants (mutations outside of protein coding genes, in non-
the regulation of cyclic AMP (cAMP-a second messenger involved in coding DNA regions) may affect expression of ASD-associated genes,
neurotransmission and memory in part through the MAPK cascade). by altering epigenetic processes such as promoters, binding sites and
By inhibiting PDE4D, cAMP levels are increased. A recent phase-2 the expression of micro RNAs (small molecules that help regulate RNA
trial in FXS found this molecule improved several endpoints related translation) (Williams et al., 2019). Last, in utero exposure to valproic
to cognition, language and daily functioning; vomiting occurred acid has been associated with ASD in humans, and is used as a mouse
more frequently in the treatment group than the placebo group model of ASD for research (Christensen et al., 2013). Valproic acid is a
(NCT03569631). In summary, early-stage trial data suggest trends to- histone deacetylase (HDAC) inhibitor; HDAC inhibitors block the forma-
wards benefits of tideglusib and BPN14770 on some ASD outcomes, tion of tightly bound ‘silenced’ chromatin normally mediated via his-
but further, large scale trials are needed to replicate results. tone deacetylase, leading to an increase in hyperacetylated ‘active/
Statins [i.e., hydroxymethylglutaryl-CoA (HMG-CoA) reductase in- open’ histones. Effectively, a small number of genes are differentially
hibitors], block cholesterol synthesis in the liver and are approved for activated or repressed during treatment with an HDAC inhibitor
the treatment of hypercholesterolemia in the general population. resulting in reduction of tumour cell growth. Pre-clinical work suggests
Statins also appear to attenuate Ras activation by blocking its that these agents may have antidepressant and pro-cognitive effects

9
D. Baribeau and E. Anagnostou Pharmacology & Therapeutics 230 (2022) 107939

also, potentially by modulating gene-environment interactions improvements than those on the gluten-free/ casein free or control
(Misztak, Pańczyszyn-Trzewik, & Sowa-Kućma, 2018). diets (El-Rashidy et al., 2017). Another open label trial (n = 15) sug-
With respect to pharmacotherapy, a novel HDAC inhibitor, AR-42, gested some improvements in ASD symptoms across several measures
showed benefits in a mouse model of Kabuki syndrome (a developmen- (Lee et al., 2018). Results are considered too preliminary for clinical rec-
tal disorder associated with intellectual disability and ASD) (Bjornsson ommendation in ASD; a large scale RCT is needed (Bostock, Kirkby, &
et al., 2014). Social deficits were significantly improved in a genetic Taylor, 2017).
mouse model of autism (SHANK3 mutation) during treatment with In summary, data on novel HDAC inhibitors are limited and largely
HDAC inhibitors (Ma et al., 2018; Qin et al., 2018). While pharmacologic preclinical. Valproic acid is sometimes used off-label for associated neu-
manipulation of chromatin remodelling may present another important ropsychiatric symptoms in ASD, when other first and second line treat-
avenue for treatment in a subset of individuals with ASD or other neu- ments have failed. Nutrient supplementation or dietary modification
rologic disorders (Fahrner & Bjornsson, 2019; Volmar & Wahlestedt, including folate derivatives, sulphoraphane or ketogenic diets show
2015), there are few existing/ approved medications available where some early efficacy signals, but require further study and large-scale
the primary mechanism of action relates to chromatin, outside of hema- replication before their clinical utility in ASD can be determined.
tological malignancies (Eckschlager, Plch, Stiborova, & Hrabeta, 2017).
Thus far, most data are preclinical. Valproic acid had mixed results in 3.4. Agents affecting synaptic function
a few small trials for treating irritability (Anagnostou et al., 2006;
Hellings et al., 2005; Hollander et al., 2010), or repetitive behaviors in The vast majority of agents trialled thus far in ASD have a primary
ASD (Hollander et al., 2006). mechanism of action at the synapse. Many historical medication clas-
Some investigators hypothesize that dietary modification and/or ses including antidepressants, stimulants, and antipsychotics have
nutrient supplementation may affect chromatin remodelling, with been examined. In general, core ASD symptoms do not substantially
therapeutic implications initially for patients with cancer or epilepsy. improve, medications are less well tolerated than in typically devel-
These treatments have recently garnered interest in ASD as well. For ex- oping patient groups, but some associated symptoms may ameliorate
ample, folate derivatives (Esse et al., 2018), sulforaphane (from broccoli (e.g., inattention/ hyperactivity, and irritability) (Ameis et al., 2018;
sprouts) (Kaufman-Szymczyk, Majewski, Lubecka-Pietruszewska, & Cortese, Castelnau, Morcillo, Roux, & Bonnet-Brilhault, 2012;
Fabianowska-Majewska, 2015), and ketogenic diets (Boison, 2017; Williams, Brignell, Randall, Silove, & Hazell, 2013). For a recent re-
Herbert & Buckley, 2013), have been suggested to affect cellular methyl- view of RCTs in ASD, including tables outlining trial details, see
ation pathways directly or indirectly. (Goel, Hong, Findling, & Ji, 2018); for trials targeting restricted and
DNA methylation requires methyl groups which are derived from fo- repetitive behaviors specifically, see (Zhou et al., 2020).
late. Animal models indicate that folate receptor antibodies may con- At the same time, many novel or repurposed agents have been
tribute to an ASD phenotype (Desai, Sequeira, & Quadros, 2017), and trialled based on the hypothesis that an imbalance in excitatory:inhibi-
that a majority of children with ASD may also have these auto- tory (E:I) signalling underlies the development of ASD. These include
antibodies (Frye, Sequeira, Quadros, James, & Rossignol, 2013). A recent excitatory glutamate modulators (acting on the excitatory NMDA,
small trial suggested that correction of nutritional deficiencies including AMPA or mGluR receptors), as well as inhibitory GABAergic agents. In
folinic acid supplementation improved ASD outcomes/ severity line with this hypothesis, many recently identified ASD-risk genes
(Ramaekers et al., 2019); other trials are underway examining folate de- have been shown to exert their effect on the synapse (Fig. 2). NRXN1
rivatives (including folinic acid/leucovorin) for core and associated for example, is a synaptic anchoring protein that also plays a role in neu-
symptoms in ASD (Table 1). rotransmission (Ching, et al., 2010); the SHANK proteins affect dendritic
Sulphoraphane is a phytochemical derived from plants, with antiox- spine formation as well as neurotransmission especially at excitatory
idant effects that may also downregulate HDAC (Kamal, Akter, Lin, & synapses (Monteiro & Feng, 2017); GRIN2B encodes a sub-unit of the ex-
Nazzal, 2020; Kaufman-Szymczyk et al., 2015). A phase-2 RCT in ASD citatory NMDA-receptor (Platzer et al., 2017); SCN2A mutations affect
suggested it reduced aberrant behavior and improved core ASD symp- sodium channel function and dendrite excitability (Spratt et al., 2019).
toms (on the SRS) and clinical global impression scores after 18 weeks Arbaclofen, for example, is the R-enantiomer of racemic baclofen (a
of treatment in adults (Singh et al., 2014). muscle relaxant). It is believed to exert its therapeutic action through
Ketogenic diets involve strict consumption of high-fat, low-protein selective GABAB receptor agonism. In animal models, it corrected abnor-
and low-carb meals, to induce a high ketone load and biochemically mal cellular morphology in dendrites in FXS (Henderson et al., 2012);
mimic aspects of starvation (Wheless, 2008). While traditionally under- arbaclofen also improved social behavior in mouse models of FXS
stood to act as mobile energy sources, ketones bodies are able to affect (Silverman et al., 2015), and 16p11.2 deletion syndrome (Stoppel
epigenetic regulation in part by inhibiting histone deacetylase (Ruan & et al., 2018). Despite some initial benefits in open label trials in ASD
Crawford, 2018). They also have cell signalling functions, can have (Erickson et al., 2013, 2014), a recent phase-2 trial in children/adoles-
anti-seizure and anti-oxidant effects, may modify GABA and glutamate cents with autism did not find a significant difference between the pla-
metabolism, have immune modulatory properties (Newman & Verdin, cebo and control groups on the primary outcome of social withdrawal,
2014; Ruskin, Murphy, Slade, & Masino, 2017), and can rapidly alter although several secondary analyses did detect differences in
the gut microbiome (David et al., 2014; Saurman, Margolis, & Luna, clinician-rated clinical global impression and socialization (Veenstra-
2020); thus, for the purposes of this review, ketogenic diets could VanderWeele et al., 2017). Side effects included affective lability and se-
equally be grouped under many biological pathways. Clinical trials dation, affecting approximately 10%. In FXS, a phase-2 RCT of arbaclofen
have found ketogenic diets to be effective for treatment refractory epi- did not meet the primary endpoint related to irritability, although other
lepsy (Neal et al., 2008; Vining, et al., 1998). Several small human and secondary measures of problem behavior and social avoidance im-
animal studies have examined ketogenic diets with respect to ASD proved (Berry-Kravis et al., 2012). Treatment was well tolerated, with
symptoms [for a systematic review see (Castro et al., 2015)]. A case se- headache and sedation as the most common adverse effects. These
ries/ pilot study of 30 children with ASD found that for the 18 that data informed two subsequent phase-3 trials (an adult study and a
remained on the diet at 6 months, most reported minor or average im- child study) where social avoidance was selected as the primary out-
provements on the childhood autism rating scale (CARS) (Evangeliou come measure. While the primary endpoint was not met, and no differ-
et al., 2003). A case report documented significant improvement in ences were detected on any measure in the adult arm, in the child study
ASD symptoms when a child was treated with a ketogenic diet for co- several secondary endpoints including irritability and parenting stress
occurring epilepsy (Herbert & Buckley, 2013). In an open label trial of showed improvement (Berry-Kravis et al., 2017). Approximately 7% of
45 children with ASD, those on the ketogenic diet showed greater those in the active treatment arm discontinued due to adverse effects

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(most commonly headache, nausea, irritability). In summary, primary anti-inflammatory properties; it also increases cysteine levels thereby
outcomes have been negative in several phase 2/3 arbaclofen trials, enhancing the activity of the cysteine-glutamate antiporter, ultimately
but there are possible trends on secondary measures suggestive of po- increasing mGluR signalling on inhibitory neurons and also increasing
tential in some subgroups. There are several trials of arbaclofen still in dopamine release (Dean, Giorlando, & Berk, 2011). Initially, a small
process (see Table 1), targeting different neurobehavioral symptom do- RCT found that NAC monotherapy was well tolerated, and improved ir-
mains that may be modifiable with this agent. Similarly, several novel ritability in ASD in children (Hardan et al., 2012). Another small RCT
agents targeting GABAA in FXS or ASD are underway (including found NAC did not improve social impairment in children with ASD
AZD7325 and RO7017773) (see Table 1). (Wink et al., 2016); neither did a larger study (n = 102) in children
Memantine is an uncompetitive NMDA antagonist that is approved with longer duration of treatment (6 months) (Dean et al., 2017). Over-
for adjunctive treatment of Alzheimer's disease. It may also have some all, however, a recent meta-analysis concluded NAC may be helpful for
activity at other receptor sites including those for serotonin, dopamine irritability, hyperactivity, and social impairment, but not repetitive be-
and acetylcholine. Despite some benefits of memantine treatment in havior, when effects were pooled across ASD trials (Lee et al., 2020).
open label trials in ASD (Chez et al., 2007; Joshi et al., 2016; Owley While sometimes used clinically given the favourable adverse effects
et al., 2006), and FXS (Erickson, Mullett, & McDougle, 2009), follow up profile, anticipated benefits are small, and multiple daily dosing of cap-
RCTs have been mostly negative. Two randomized controlled trials sules may present a barrier to treatment. Amantadine is an agent used
have not shown significant improvements on primary endpoints related to treat Parkinson's disease; it antagonizes the NMDA receptor and the
to core ASD symptoms domains (SRS) (Aman et al., 2017; Hardan et al., nicotinic receptor, while acting as an agonist for dopamine. In ASD,
2019). Secondary measures also showed no differences in one of the tri- treatment with amantadine showed no significant difference on pri-
als (Aman et al., 2017), while an open label extension did find benefits mary endpoints related to parent-rated irritability, although secondary
on the SRS (Hardan et al., 2019). While the treatment was generally endpoints including clinician-rated hyperactivity, inappropriate speech
well tolerated, there was a higher incidence of irritability and aggression and global improvement showed differences in favor of amantadine
compared to placebo (affecting <10%) (Aman et al., 2017). One trial also (King et al., 2001). Given some data suggestive of benefit for hyperactiv-
suggested memantine may be beneficial as an adjunct to ABA therapy ity in ADHD, some clinicians occasionally use amantadine off-label to
(Karahmadi, Tarrahi, Vatankhah Ardestani, Omranifard, & Farzaneh, treat comorbid psychiatric symptoms and hyperactivity in ASD
2018). There is also theoretical and preclinical data suggestive that (Hosenbocus & Chahal, 2013). D-cylcoserine is a NMDA partial agonist;
memantine may be specifically helpful in individuals with GRIN2B mu- when paired with a behavioral social skills group intervention (10
tations which affect NMDA receptor function (Platzer et al., 2017). In weeks), a recent trial found greater maintenance of improvement on
FXS, an RCT found no benefits on primary or secondary endpoints re- the social responsiveness scale compared to those receiving placebo at
lated to tremor or executive function in individuals with Fragile X asso- 22 weeks (Wink et al., 2017), but no difference during the acute treat-
ciated tremor-ataxia syndrome (FXTAS) (Seritan et al., 2013), although ment phase (Minshawi et al., 2016).
memantine appeared to improve specific EEG parameters and certain Bumetanide is a potent diuretic that may indirectly increase
cognitive measures (memory, attention) in another small trial in GABAergic inhibition by reducing intracellular chloride; initially, a
FXTAS (Yang et al., 2014; Yang et al., 2016). While published data to case series and a pilot study suggested some benefits for core ASD
date appear mostly negative with respect to ASD-associated endpoints, symptoms in children (Du et al., 2015; Lemonnier & Ben-Ari, 2010).
several additional trials of memantine in ASD are in process (see Two follow up RCTs found reduction in core ASD symptoms and in-
Table 1), creased facial emotion recognition on several measures (including the
Ketamine is another NMDA antagonist with renewed interest as a SRS, CARS and CGI) within specific subgroups (e.g., the less severely af-
therapeutic in neuropsychiatry given its ability to induce a rapid anti- fected, or study completers) (Lemonnier et al., 2012; Lemonnier et al.,
depressant effect. It has a unique mechanism of action including block- 2017). Two more recent trials had conflicting results; a trial in younger
ade of open NMDA receptors and modulation of their firing frequency, children (ages 3–6 years, n = 83) found clinical improvement on their
with downstream effects on pathways including mTOR, brain derived primary outcome of core ASD symptoms on the CARS for 81 out of 83
neurotrophic factor, and AMPA (Zanos & Gould, 2018). It is used clini- trial completers (Zhang et al., 2020). However, a trial in older chil-
cally for procedural anesthesia. Despite a few case reports showing dren/youths (age 7–15 years, n = 92) was negative on the primary out-
acute benefits in ASD (Kastner, Walsh, Shulman, Alam, & Flood, 2016; come (using the SRS), analyzed using the intention to treat group
Wink et al., 2014), a recent randomized, controlled cross-over trial assignments; secondary endpoints suggested significant differences in
found no differences in their primary outcome of social withdrawal or repetitive behavior but not irritability or sensory hyper/hyposensivitiy
on other ASD-related behavioral scales (e.g., CGI, SRS) after receiving (Sprengers et al., 2021). A very recent randomized controlled trial in a
two doses of intranasal ketamine (Wink et al., 2020). Treatment was larger sample of 3–6 year olds (n = 120) suggested Bumetanide signif-
generally well tolerated, with some transient changes in heart rate/ icantly reduced core ASD symptoms on their primary outcome measure
blood pressure during active treatment observed. of the CARS, with a trend on the CGI-I and significant benefit on the SRS
A series of other compounds that modulate glutamate have also as well (Dai et al., 2021). The medication was generally well tolerated,
been investigated in ASD. Riluzole, for example, is an agent approved with polyuria being the most common side effect (67%); some electro-
for treatment of amyotrophic lateral sclerosis; it modulates glutamate lyte abnormalities occurred as well. However, group differences on the
uptake and release, and blocks sodium and NMDA receptors. A small CARS were modest (1 point difference in improvement out of a possible
RCT found no difference in ASD- associated irritability on primary or 60-points), and the trial was conducted at a single site only. Across all
secondary measures following treatment with riluzole; the medication bumetanide trials, blinding of treatment assignment is especially chal-
was well tolerated with no significant differences in adverse effects be- lenging given the side effect profile (hypokalemia- requiring potassium
tween treatment groups (Wink et al., 2018). Another trial found riluzole supplementation, as well as polyuria), which may inflate placebo re-
did have the capacity to shift frontal connectivity and inhibitory tone on sponses and bias parent and clinician rated outcome assessments.
neuroimaging parameters (Ajram et al., 2017). In an open label trial in Mechanistically, bumetanide increased eye contact in an experimental
FXS, one of 6 participants improved with respect to ADHD symptoms paradigm, normalized functional neuroimaging differences in the
(Erickson et al., 2011). Other trials have recently completed amgydala (Hadjikhani et al., 2018), and response to treatment corre-
(NCT01661855). N-acetyl-cysteine (NAC) is commonly prescribed lated with decreases in the GABA to glutamate ratios in the insular
treatment for acetaminophen overdose, and is available as a dietary and visual cortices (Dai et al., 2021; Zhang et al., 2020). Despite some
supplement. It has several mechanisms of action: it is a precursor to positive outcomes in bumetanide RCTs, methodological questions,
the antioxidant glutathione, therefore reduces oxidative stress; it has multi-site replication, and need for clarity on the risk to benefit ratio

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D. Baribeau and E. Anagnostou Pharmacology & Therapeutics 230 (2022) 107939

of treatment, especially in small children, are needed before this agent core ASD symptoms (on the SRS) as well as secondary measures of anx-
can be considered for routine clinical use. iety and repetitive behavior (Parker et al., 2019).
In summary, numerous agents targeting synaptic processes have Immunologic mechanisms in ASD have received increased atten-
been trialled for core ASD symptoms. Most require additional data be- tion in the past few years. This hypothesis is supported by research
fore conclusions can be made regarding their clinical utility in ASD. identifying the innate immune system as playing an important role
NAC and amantadine are sometimes used off-label to target ASD- shaping prenatal CNS development (Deverman & Patterson, 2009;
associated symptoms (irritability, and ADHD-symptoms, respectively). Estes & McAllister, 2016). Maternal infection during pregnancy has
Despite several large trials of bumetanide suggesting benefit, further emerged as an ASD risk factor in some (Al-Haddad et al., 2019;
data are needed before recommendations can be made about this agent. Atladóttir et al., 2010; Hornig et al., 2018), but not all (Atladóttir,
Henriksen, Schendel, & Parner, 2012; Zerbo et al., 2017), epidemiologic
studies, with data highlighting fever/ severe infection/ hospitalization,
3.5. Other systems: Neuropeptides and immune and second trimester exposure as potentially higher risk [for a review
see (Careaga, Murai, & Bauman, 2017)]. Mothers of children with ASD
While approximately 50% of cases of ASD are thought to be attribut- had higher level of several inflammatory cytokines mid-pregnancy
able to a genetic origin (either specific rare variants, common polyge- (Jones et al., 2017), data are conflicting regarding C-reactive protein
netic risk, or a combination of the two),(Weiner et al., 2017) other (Brown et al., 2014; Zerbo et al., 2016). Children with autism may
mechanisms and pathways for the remaining 50% of cases may also have higher levels of pro-inflammatory cytokines in the serum
present targets for pharmacotherapy. Data driven analyses of RNA (Kordulewska et al., 2019; Saghazadeh et al., 2019b), and lower levels
gene expression networks in brain tissue have highlighted the impor- of anti-inflammatory cytokines (Saghazadeh et al., 2019a). Conclusions
tance of the oxytocin and vasopressin neuropeptide system across are limited by data suggesting significant variability in cytokine and
the whole brain, and that the disruption of proteins involved in im- chemokine levels within the same individual over time, significant ef-
mune function (astrocytes and microglia) in particular may play a fects of age and gender, and lack of correlation between serum and
role in ASD (Hartl et al., 2020). CSF levels (Pardo et al., 2017). Elevated inflammatory profiles in neona-
The neuropeptide theory of social behavior has emerged from an tal blood spots were associated with future ASD risk as well (Heuer
extensive body of animal work based initially on experiments done in et al., 2019). Animal models with induced maternal infection/ inflam-
rodents (specifically voles). The mechanisms, rationale and initial opti- mation during gestation have demonstrated neurobehavioral sequelae
mism surrounding neuropeptide manipulation as a treatment for social in offspring (Careaga et al., 2017).
deficits in ASD have been extensively reviewed elsewhere [see With respect to treatment implications, patients who had ASD in the
(Baribeau & Anagnostou, 2015; Guastella & Hickie, 2016; Meyer- context of autoimmune encephalitis appeared to benefit from intrave-
Lindenberg, Domes, Kirsch, & Heinrichs, 2011)]. In brief, oxytocin and nous immunoglobulin for behavioral symptoms in an open label case
vasopressin are pituitary neuropeptides involved in parturition/ milk- series (Connery et al., 2018). Pioglitazone is medication that agonizes
letdown and water homeostasis, respectively; there is some receptor peroxisome proliferator activated receptor (PPAR)-ϒ (a nuclear hor-
cross reactivity between molecules. The mating patterns of voles (mo- mone receptor); in addition to affecting insulin sensitivity, it has been
nogamous vs. polygamous behavior), were found to reflect the concen- found to have anti-inflammatory properties including reduction of pro-
tration and distribution of oxytocin receptors in their basal forebrains, inflammatory cytokines (Wu, Zhao, Chu, & Ye, 2010). A recent pilot and
and to be modifiable with neuropeptide administration (Insel & dose finding study in ASD found evidence of improvement in external-
Shapiro, 1992; Williams, Carter, & Insel, 1992). The neuropeptide theory izing behavior, repetitive behavior, and global response (Capano et al.,
is further supported by data suggesting that some social abilities 2018). The trial was small (n = 25), uncontrolled, and single blinded;
(e.g., theory of mind) may correlate with plasma oxytocin levels, and a large scale RCT is now needed to confirm these early efficacy signals
that common genetic variation in the oxytocin receptor gene (OXTR) and further examine safety/ tolerability. In this small sample, pioglita-
may be associated with social deficits to some degree (Baribeau et al., zone was well tolerated with no serious adverse effects reported across
2017; Parker et al., 2014). all dose ranges; no patients discontinued due to adverse effects. The
Initial experiments in typically developing humans showed that most common reported adverse effects (n > 5) during treatment in-
oxytocin infusion had the potential to increase trust in a gambling exer- cluded upper respiratory tract infection, tooth problems, irritability/ ag-
cise (Kosfeld, Heinrichs, Zak, Fischbacher, & Fehr, 2005); over a dozen gression and insomnia. Similarly, polyunsaturated fatty acids, such as
trials examining intranasal oxytocin as treatment for social deficits omega 3 also have anti-inflammatory properties and may be involved
and/or repetitive behavior in ASD have emerged in the past decade, in maintaining cell membranes and myelin sheaths. In ASD, two meta-
with several additional trials underway (Table 1). Recent meta- analyses suggest potential small benefits for social withdrawal/ lethargy
analyses suggest possible small, albeit non-significant effects when (Cheng et al., 2017; Horvath, Łukasik, & Szajewska, 2017), hyperactivity
data are pooled, primarily in the social domain (Ooi, Weng, and stereotyped behavior (Cheng et al., 2017). However, in a trial in
Kossowsky, Gerger, & Sung, 2017; Wang, Wang, Rong, He, & Yang, young children (under 5 years) with ASD, treatment with omega-3
2019). Optimal timing, route and dose of oxytocin administration re- fatty acid for 6 months did not improve primary or secondary outcomes
main unclear, with some studies treating children for 6 months with in- related to ASD symptoms or adaptive behavior; in fact, data suggested
tranasal oxytocin alongside a behavioral intervention, while others have treatment was associated with worsening of externalizing behavior in
examined social performance after a single intravenous dose. Long term this group (Mankad et al., 2015). A number of other agents (including
intranasal oxytocin appears to be associated with minimal adverse ef- valproic acid and NAC listed above) may also have immune modulatory
fects (Cai, Feng, & Yap, 2018). Vasopressin receptor antagonists have or anti-inflammatory properties as potential mechanisms of action
also been investigated as novel therapeutics in ASD; given receptor [reviewed in (Thom & McDougle, 2020)]. Several trials examining
cross-reactivity, blockade of vasopressin receptors is thought to en- agents with immunologic mechanisms (e.g., steroids, antibiotics, anti-
hance oxytocin signalling. A recent large randomized controlled trial oxidants) are in process (Table 1). At present, there are very early sig-
of balovaptan (oral AVPR1a selective antagonist) in adult males with nals of efficacy for pioglitazone, and conflicting data for omega-3; thus
ASD found no difference on the primary endpoint (SRS) but found im- further data and large-scale RCTs are needed to determine the efficacy
provements on secondary measures of adaptive behavior (Bolognani and safety of immune modulatory agents for treatment of core ASD
et al., 2019). Treatment was well tolerated, without orthostatic changes symptoms.
in blood pressure or blood values. A smaller trial of intranasal vasopres- A related hypothesis, gut dysbiosis, proposes that an imbalance in
sin in children with ASD found improvement in the primary endpoint of gut microflora in ASD leads to inflammatory changes and dysregulation

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D. Baribeau and E. Anagnostou Pharmacology & Therapeutics 230 (2022) 107939

of the “gut-brain axis," thereby influencing behavior (Vuong & Hsiao, health and developmental pathology (Cleynen, et al., 2020; Davies
2017). For example, mice raised in a germ-free environment had abnor- et al., 2020), and may help elucidate biological processes of relevance
mal social behaviors and social avoidance, which was partially im- to drug discovery, and to idiopathic/essential autism (e.g., polygenic
proved with bacterial colonization of the gut (Desbonnet, Clarke, risk). Beyond novel therapeutics, systematic efforts to study the re-
Shanahan, Dinan, & Cryan, 2014). Maternal diet has been shown to in- sponse/tolerability of traditional psychotherapeutic agents in genetic
fluence gut microflora in animal models (Buffington et al., 2016); probi- subtypes of ASD is greatly needed and may help accelerate the clinical
otic treatment corrected some abnormalities (Buffington et al., 2016; translation of genomics research. So far, data are sparse/ non-existent
Hsiao et al., 2013). The gut microbiome has also been found to be impor- to guide the choices of existing psychopharmacology in the setting of
tant for shaping overall immunity (Hooper, Littman, & Macpherson, a known genetic diagnosis. While large consortia and international col-
2012; Round et al., 2011). A small open label trial suggested that laborations are vital to amass databases sufficient for clinical prediction
bowel cleanse followed by fecal microbiota transplant improved gastro- and precision health care in the setting of advancing genetic technolo-
intestinal symptoms, behavioral symptoms, and ASD symptoms concur- gies (Costain, Cohn, & Malkin, 2020), astute clinical observation and
rently (Kang et al., 2017), and that improvements persisted at 2 years case series' may be additionally informative with respect to identifying
(Kang et al., 2017); although without a control group, conclusions are subgroups differentially responsive to treatment. As an example, pedi-
limited. Probiotics appear to be well tolerated in ASD (Sanctuary et al., atric epilepsy is now recognized to comprise specific genetic subtypes
2019). In ulcerative colitis trials, fecal microbiota transplant was gener- that may be uniquely responsive or non-responsive to traditional anti-
ally well tolerated, although serious adverse events including bowel convulsant medications (e.g., avoid sodium channel blocking medica-
perforation, bowel resection and c-difficile infection were reported tions in SCN1A-related Dravet syndrome, treat GLUT1 deficiency
(Dang, Xu, Liu, Zhou, & Yang, 2020). Several randomized controlled tri- related epilepsy with ketogenic diets in lieu of pharmacotherapy).
als examining fecal transplant, probiotic treatment, and other immune Therefore, while traditional treatment algorithms still apply for the
modulators are currently underway (see Table 1); in the absence of ran- vast majority of pediatric seizures, genetic testing has important clinical
domized controlled trials showing efficacy and assessing safety/tolera- sequelae for a minority of cases. Further work into novel trial designs for
bility in ASD, these treatments are not currently recommended, rare disease [e.g., serial n of 1, Bayesian analysis, master observational
however. trials (Dickson et al., 2020)] may help facilitate drug discovery for rare
forms of ASD. Large scale clinical cohorts in ASD with genomic data
4. Future considerations and next steps may also consider incorporating measures of pharmacologic response/
tolerability as secondary endpoints.
Moving forward with drug discovery for ASD requires ongoing inno- With respect to trial design, it is widely hypothesized that there are
vation and collaboration with respect to outcome measurement, geno- treatment responsive (or non-responsive) subgroups with unique bio-
mics, clinical care and trial design. logical or behavioral profiles in ASD that have yet to be discovered,
With respect to outcome measurement, ongoing investigation into and therefore trialists are encouraged to include a wide array of bio-
ideal behavioral targets and associated biomarkers is needed. Currently markers as part of phenotyping protocols (Beversdorf & Missouri
trials are constrained by regulators to using caregiver surveys targeting Autism Summit, 2016). Alternatively, it is possible that reducing genetic
core ASD symptoms (social and restricted/repetitive behavior), which heterogeneity by studying medication response in specific subpopula-
are complex, environmentally embedded and can vary by context. Ulti- tions (e.g., those with a particular rare CNV, single gene disorder, or
mately, it may be that meaningful change in these domains requires even complex vs. essential ASD) could increase the signal-to-noise
prolonged treatment, application very early in development [even pre- ratio. Heterogeneous responses even within specific genetic syndromes
natally? (Satterstrom, et al., 2020)], or combinations with psychosocial have been observed, however. For example, in Lesch-Nyhan disease (an
and environmental interventions. Alternatively, agents found to im- X-linked developmental disorder associated with ASD and severe self-
prove other more direct behavioral targets (e.g., memory, cognition), injurious behavior), a small RCT of 10 individuals was stopped early
associated symptoms (irritability), or upstream pathobiology (specific due to tolerability concerns, yet one participantwas strikingly and per-
circuits, functional connectivity, E:I balance), may prove equally helpful sistently responsive to treatment with a novel D1 dopamine antagonist
with respect to functional outcomes. (Khasnavis et al., 2016). At the same time, investigators could consider
At the same time, rigorous design and validation of outcome mea- incorporating systematic efforts to measure and test of heterogeneity
sures specifically to capture change in ASD core symptom domains for of treatment effects (HTE) in ASD trials or on meta-analyses (Kent,
use as trial endpoints, with validity across diverse clinical samples, Rothwell, Ioannidis, Altman, & Hayward, 2010). HTE effectively tests
and that are not overly sensitive to other behavioral fluctuations or pla- whether the variance in the treated group is larger than the variance
cebo, will be needed to address measurement shortcomings. [The Au- in the placebo group, essentially treating variation in response to medi-
tism Impact Measure (AIM) is an example of a newer measure cation as an endpoint. In lieu of various post-hoc subgroup analyses,
designed for this purpose (Kanne et al., 2014)]. Scientific panels confirming HTE provides statistical support for the hypothesis that
(Beversdorf & Missouri Autism Summit, 2016), granting agencies and there are subgroups of treatment responders or non-responders, while
advocacy groups have recognized the need for novel, performance- preserving statistical power. Schizophrenia is a condition with substan-
based outcome measures or biomarkers in ASD; projects examining tial clinical and etiological heterogeneity similar to ASD; despite early
eye-tracking software (Frazier et al., 2018), computerized task- hypotheses, recent analyses have not identified heterogeneity in re-
completion, and brief social observations (Grzadzinski et al., 2016), sponse to antipsychotic treatment (McCutcheon et al., 2019; Mizuno,
have been funded, for example. Consideration of other novel design McCutcheon, Brugger, & Howes, 2020).
and analytic approaches to outcome measurement, including patient- Advances in scientific technologies related to gene editing a may also
centered problem definitions and narratives (Scahill et al., 2017), or yield subsequent clinical application with respect to novel therapies in
item response theory (IRT) to identify the most discriminative items ASD. For example, manipulation of the CRISPR/Cas9 adaptive immune
across clinical populations (Haem, Doostfatemeh, Firouzabadi, system (CRISPR- clustered regularly interspaced short palindromic re-
Ghazanfari, & Karlsson, 2020; Sturm, Kuhfeld, Kasari, & McCracken, peats) using short RNAs has facilitated direct and precise genomic
2017; Yang & Kao, 2014) may merit exploration. Prioritizing and editing, and even repair, within mammalian genomes (Cong et al.,
funding measurement research in ASD is vital to ensuring precise and 2013). The implications of these technologies for ASD are widespread
efficient trial design and implementation. and yet to be fully realized. The rapid development of numerous ASD
Rare genetic disorders/variants associated with ASD can be helpful model organisms (mice, primates, zebra fish, etc.), is one example,
as a model for studying etiopathologic mechanisms underlying mental which has facilitated further understanding of genotype-phenotype

13
D. Baribeau and E. Anagnostou Pharmacology & Therapeutics 230 (2022) 107939

associations and subgrouping based on pathobiology (Ellegood et al., Declaration of competing interest
2015). Interestingly, several genetic animal models of ASD have
emerged where the heterozygous mutations carriers (+/−) (as op- Dr. Anagnostou has received consultation fees from Roche and
posed to full gene knock-out, −/−) also display an ASD phenotype Quadrant, research funding from Roche, in-kind supports from AMO
[e.g., SHANK3 (Zhou et al., 2016), TSC1 (Tsai et al., 2012)]. These pharma, editorial Honoria from Wiley and book royalties from APPI
haploinsufficient mice may more closely resemble the pathobiology of and Springer. She holds a patent for the device, “Tully” (formerly
autosomal dominant conditions in humans and may present an oppor- Anxiety Meter). She has received royalties from APPI and Springer.
tunity for screening of novel therapeutics. Along the same line, the dis- Dr. Baribeau has no conflicts to declare.
covery that induction of pluripotent stem cells is possible from skin or
blood tissue has facilitated advanced invitro models of neurons and References
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