The document summarizes recent advances in the management of autism spectrum disorder (ASD). It discusses updates to diagnostic classifications in ICD-11 that incorporate autism and Asperger's syndrome. It also outlines recent diagnostic tests and screening tools. For treatment, it discusses pharmacological advances including mTOR inhibitors, arginine vasopressin pathways, bumetanide, and pharmacogenomics. It also discusses behavioral interventions such as naturalistic developmental behavioral interventions and the potential for early detection of signs at 6 months of age.

1. RECENT ADVANCES IN
MANAGEMENT OF
ASD
Guided by – Dr Abhay Paliwal Sir
Associate Professor
Department of Psychiatry
MGMMC and MYH

2. RecentAdvances
■ Nosology
■ Diagnosis
■ Treatment
– Pharmacological
– Pharmacogenomics
– Behavioural
– Miscellaneous

3. NOSOLOGY

4. Nosology
■ InternationalClassification of Dieases‐11 (ICD-11) neurodevelopmental disorders
encompass the ICD‐10 groupings of mental retardation and disorders of psychological
development, with the addition of attention deficit hyperactivity disorder (ADHD).
■ Autism spectrum disorder in the ICD‐11 incorporates both childhood autism and
Asperger's syndrome from the ICD‐10 under a single category characterized by social
communication deficits and restricted, repetitive and inflexible patterns of behaviour,
interests or activities.

5. Nosology
■ Guidelines for autism spectrum disorder have been substantially updated to reflect
the current literature, including presentations throughout the lifespan.
■ Qualifiers are provided for the extent of impairment in intellectual functioning and
functional language abilities to capture the full range of presentations of autism
spectrum disorder in a more dimensional manner.

6. Nosology
■ The update signifies shift from considering autism as a neurodevelopmental disorder
rather than disorder of psychological development.
■ The changes in ICD-11 are more in lines with the current DSM-5

7. DIAGNOSIS

8. Diagnosis
■ Tests are complementary to the clinical evaluation and could be useful to complete
the assessment, but an incorrect use of a test could lead to a misdiagnosis,ASD over-
or under-diagnosing.
■ According to the current diagnostic manuals, such as the ICD-11 and the DSM-5, the
final diagnostic decision is clinical, based on the core symptoms of ASD.
■ Standardized instruments may help to detect autism and prompt a more
comprehensive assessment but must be distinguished if they are instruments of
screening or instruments for diagnosing or for evaluating the functioning.

9. Diagnosis
Test for ASD screening:
■ they must not be used for diagnosing but only for screening or for research
purpose.
■ AQ-autism quotient, EQ-empathy quotient (Baron-Cohen), self-report, useful for ASD
level 1 DSM-5 and especially for Asperger disorder; ASD must have good awareness of
their behavior.
■ The Autism Spectrum Disorder—Diagnosis Scale for Intellectually DisabledAdults
(ASD-DA) is a structured interview that is used to screen for ASD in adults with
intellectual disability.

10. Diagnosis
■ Social Communication Questionnaire (SCQ) is a third-party assessment tool
developed for children and adolescents.
■ The Autism Checklist (ACL) is a screening tool based on the ICD-10 research
criteria. It facilitates a structured medical history and assessment in medical
visits.
■ The Diagnostic Behavioral Assessment for ASD-Revised (DiBAS-R) is an ICD-
10/DSM-5-based caregiver report screening tool that consists of 19 Likert-scaled
items.
■ The Psychiatric Instrument for the Intellectually Disabled Adult (SPAID) is for the
diagnostic assessment in adults with ID. It consists of a general form and specific
checklists for certain disorders, including ASD.

11. Diagnosis
■ Test for ASD diagnosing
■ The Autism Diagnostic Interview—Revised (ADI-R) is a semi-structured parental
interview assessing social reciprocity, communication, and restrictive, repetitive
behaviors between the ages of 4 and 5 years.
– It consists of 93 Likert-scaled items, and a selection of these is adopted by the final
algorithm, resulting in a classification of “autism” or “no autism.”
– Is useful especially for typical autism but could be false negative in AS because
symptoms are recognized later at the school time;
– another limit of its use is related to the age of the patient and particularly the age of the
parents because the evaluation is based on the memory of first years of life and of the
timing of the neurodevelopmental step.

12. Diagnosis
■ The Autism Diagnostic Observation Schedule (ADOS) is a semistructured
observation tool to assess social communication in persons suspected of having
ASD.
– Depending on their verbal abilities, one of four modules can be applied, and generally
module IV is used in adulthood. It is useful in typical form of autism but not in severe
level of autism or in AS.
■ RAADS (Ritvo Autism Asperger Diagnostic Scale Revised), an assessment for Asperger
disorder; it is free of charge and available online.
■ After diagnosis of ASD, a functional assessment should be completed using for example
Vineland II,VB-MAPP,TTAP.

13. TREATMENT
Pharmacological

14. Pharmacological advancements
■ The contemporary pharmacological agents forASD include antidepressants,
antipsychotics, and psychostimulants, aimed at symptoms such as hyperactivity,
aggression, self-injurious behavior, impulsivity, stereotypies, mood disorders, and
anxiety.
■ Currently, there is a trend to investigate more specific pharmacological agents to
improve social functioning in patients with ASD.
■ Neurobiological systems that are crucial for social functioning are conceivably the
most encouraging signalling pathways for ASD therapeutic discovery.

15. Naltrexone
■ Naltrexone has been used most commonly at doses ranging from 0.5 to 2 mg/kg/day
and found to be predominantly effective in decreasing self-injurious behavior.
■ Naltrexone may also attenuate hyperactivity, agitation, irritability, temper tantrums,
social withdrawal, and stereotyped behaviors.
■ Patients may also exhibit improved attention and eye contact.Transient sedation was
the most commonly reported adverse event.

16. Naltrexone
■ Possibilty that endogenous opioid cause social withdrawal and unusual sensitivity
to environment.
■ The endogenous opioid system is well known to relieve pain and underpin the
rewarding properties of most drugs of abuse.
■ Among opioid receptors, the μ receptor mediates most of the analgesic and rewarding
properties of opioids.
■ Based on striking similarities between social distress, physical pain and opiate
withdrawal, μ receptors have been proposed to play a critical role in modulating social
behaviour in humans and animals.

17. Naltrexone
■ The μ opioid receptor balance model, to account for the contribution of μ receptors to
the subtle regulation of social behaviour.
■ Interestingly, μ receptor null mice show behavioural deficits similar to those observed
in patients with autism spectrum disorder (ASD), including severe impairment in social
interactions.

18. Pellissier LP, Gandía J, LabouteT, Becker JAJ, Le Merrer J. μ opioid receptor, social behaviour and autism
spectrum disorder: reward matters. Br J Pharmacol. 2018;175(14):2750-2769. doi:10.1111/bph.13808

19. mTOR andTSC inhibitors
■ Half of the cases with tuberous sclerosis are found to be having autism.
■ Role ofTSC1 andTSC2 genes in autism have also been implicated for over a decade.
■ New studies are being stressed to find out the molecular pathways that result in ASD.

21. mTOR andTSC inhibitors
■ Interestingly, rapamycin a novel drug used for treatment of tuberous sclerosis and
other related neoplastic conditions is also being considered for use in ASD.
■ According to Zhou, et al., chronic administration of rapamycin from an early postnatal
period onward prevented brain enlargement and neuronal soma hypertrophy and
alleviated axonal and dendritic hypertrophy.
■ This treatment kept the mutant mice in a generally healthy condition as long as the
treatment continued, and it prevented phenotypic abnormalities observed in the
nontreated mutants, such as impaired social interaction, elevated anxiety, and the
development and worsening seizures.

22. mTOR andTSC inhibitors
■ In the clinical trial of sirolimus for renal angiomyolipomas accompanied byTSC and
lymphangiomyomatosis with or withoutTSC, immediate recall memory and executive
function of the participants showed a substantial improvement after sirolimus
treatment.
■ Everolimus reduced seizure frequency in individuals withTSC with or without
subependymal giant cell astrocytoma.
■ Moreover, quality-of-life scores, particularly on items related to ASD symptoms,
significantly increased after the treatment. Based on these promising results, several
clinical trials are under way testing mTOR inhibitors for neurocognitive deficits inTSC

23. Arginine vasopressin pathways (AVP)
■ The arginine vasopressin (AVP) signalling pathway is one of the most promising ones.
■ Many preclinical studies have shown the importance ofAVP physiology in social
functioning in several mammalian species.
■ Furthermore, variants in the adjacent oxytocin-vasopressin gene regions have been
found to be associated with ASD diagnosis.
■ More researches are hence being directed towards AVP and the molecules associated
with it

24. Arginine vasopressin
■ It plays a crucial role in organizing social behaviors such as social recognition and
sexual behavior
■ Repetitive behaviors are probably influenced by AVP since it is considered to be a
neuromodulator, targeting the amygdala, hippocampus, striatum, hypothalamus, and
nucleus accumbens.
■ Irregularities of AVP inASD can be attributed to different reasons, such as a decrease
in hormonal levels due to reduction in synthesis, changes in hormonal delivery,
receptor abnormalities, or an alteration of the glia and/or accelerated synaptic
shearing

25. Arginine vasopressin
■ The role of AVP in individual social memory processing was initially found in male and
female rats and male mice.
■ Several studies were conducted in animal models using different routes of
administration ofAVP.
■ Acute intranasalAVP (IN-AVP) administration in animal models has shown different
results on pro-social effects
■ Other animal studies have used different routes of AVP administration other than
inhalation

26. Arginine vasopressin
■ Thus far, there have been few human studies that deal with vasopressin and autism.
■ University of Stanford are currently conducting a double-blind, randomized, placebo-
controlled, parallel design testing the efficacy and tolerability of a 4 week intranasal
AVP treatment in a sample of n = 30 children with ASD, aged 6–12 years

27. Balovaptan
■ code name RG7314
■ It is a selective small molecule antagonist
■ It acts on vasopressinV1A receptor
■ under development by for the treatment of autism.
■ The FDA granted this based on the results of the adult phase II clinical trial called
VANILLA (VasopressinANtagonist to Improve sociaL communication in Autism) study
■ As of August 2019, it is in a phase III clinical trial for adults and a phase II clinical trial for
children for this indication.

28. Bumetanide
■ The loop diuretic bumetanide appears to improve some of the core behavioral
symptoms of autism.
■ In DSM-5, sensory symptoms are the core diagnostic feature of ASD, which has
focused increasing attention on these symptoms. Atypical sensory experience occurs
in almost 90% of autistic individuals and affects every sensory modality.

29. Bumetanide
■ More broadly, studies have shown that sensory symptoms not only precede but also
are predictive of social-communication deficits in childhood, as well as eventual
diagnostic status, indicating impaired sensory traits may serve as early biomarkers of
autism.
■ E-I imbalance has been posited to be the neurobiology of autistic sensory impairment

30. Bumetanide
■ The loop diuretic bumetanide appears to improve some of the core behavioral
symptoms of autism.
■ Bumetanide has been reported to alter synaptic excitation–inhibition (E-I) balance by
potentiating the action of γ-aminobutyric acid (GABA), thereby attenuating the
severity of autism spectrum disorder (ASD) in animal models.
■ However, clinical evidence of its efficacy in young patients with ASD is limited.

31. TREATMENT
Pharmacogenomics

32. Pharmacogenomics
■ Rapid advances in technologies have empowered genomic studies to deliver a growing
body of knowledge of pathophysiological mechanisms underlying ASD
■ Current pharmaceutical treatments, such as antipsychotics, SSRIs, and stimulants,
have thus far targeted noncore symptoms, such as irritability, aggressive behaviors,
and repetitive behaviors, etc.
■ However, the long-term use of these psychotropic medications may cause some
metabolic and cognitive adverse effects in some individuals.

33. Pharmacogenomics
■ The concerns about these side effects constantly impact the medication compliance
and hence lead to symptom relapse—which is a common challenge in clinical
management for youth with psychiatric disorders.
■ Hence, genetic information that can predict the response or likelihood of side effects
may optimize the clinical decisions that address the risk-benefit ratio.
■ In addition, most previous efforts to evaluate novel pharmacological treatments for
the core feature of ASD have failed.

34. Pharmacogenomics
■ The failure to develop effective pharmacological treatments may be attributable to
the complex genetic architecture of ASD; therefore, a compound that targets a single
or a few neurotransmitters may have difficulty normalizing perturbed neural functions
causing core social deficits.
■ However, such challenges also present opportunities for the development of novel
pharmacological treatment options.
■ Understanding how genetic liability modifies the effect of drugs may present an
opportunity to address the challenges of personalized medicine in autism.

35. TREATMENT
Behavioural Interventions

36. Early signs
■ Prodromal symptoms of ASD at 6 months include a diminished ability to attend spontaneously
to people and their activities.
■ Infant Neural Sensitivity to Dynamic Eye Gaze Is Associated with Later Emerging Autism.
■ Attention to Eyes is Present But in Decline in 2–6 Month-Olds Later Diagnosed with Autism
■ Head Lag in Infants at Risk for Autism

37. Behavioural interventions
■ The past decade has produced a wealth of evidence on very early risk markers for ASD,
often ascertained through longitudinal studies of infant siblings of children with ASD.
■ Newer studies have succeeded in identifying behavioral risk markers as early as 12
months of age in this high-risk group.The age of risk detection is moving even
younger, with some evidence of developmental or neurological differences in babies
as young as 6-9 months of age who later receive an ASD diagnosis.

38. Behavioural interventions
■ Early differences have been reported in several core developmental domains including
sensory-motor, attentional, social-emotional, and communication domains.
■ Advances in early detection have, for the first time, raised the possibility of very early
intervention, which will allow us to capitalize on neural plasticity during key
developmental windows.

39. Naturalistic Developmental Behavioral
Interventions
Measures in NDBI are based on three core techniques
■ Nature of the LearningTargets
■ Nature of the LearningContexts
■ Nature of the Development-Enhancing Strategies

40. Naturalistic Developmental Behavioral
Interventions
■ Nature of the LearningTargets
– emphasize the integration of knowledge and skills across developmental domains
and promote generalization of newly learned skills at every phase of the
intervention process.
– Example
learning a symbol, such as a new word or gesture, in one
activity
using the word or gesture to sustain engagement with
another person and in other activities
integrated with development of skills in other domains

41. Naturalistic Developmental Behavioral
Interventions
■ Nature of the Learning Contexts
– The empirical literature has documented that children’s experiences affect their
neurobiological development and that experiences have a cascading effect on
development.
– The contexts within which early learning occurs need to allow children to experience the
natural contingencies of their own behavior.
– Increasing evidence is emerging that learning is enhanced when it is embedded in
activities that contain emotionally meaningful social interactions compared to situations
in which instruction occurs without meaningful social engagement.
– Within NDBIs, this is often accomplished through establishing adult-child engagement
activities that transform into motivating play routines or familiar daily life routines.

42. Skill development is based on adult-child interaction which involves routines and experiences
already familiar to the child.

43. Naturalistic Developmental Behavioral
Interventions
■ Nature of the Development-Enhancing Strategies
– The development-enhancing strategies used within the NDBIs work together to
support high levels of success inside ecologically valid contexts, routines and
materials within them.
– The development-enhancing strategies used within the NDBIs work together to
support high levels of success inside ecologically valid contexts, routines and
materials within them

44. Naturalistic Developmental Behavioral
Interventions
■ Nature of the Development-Enhancing Strategies
– For example, a playful routine involving tickles when putting on the child’s shirt
during a dressing routine may be expanded to include receptive language skill
building as well as social commenting.
– The child may be instructed to follow directions to ‘get your shirt’, where he must
select the shirt from an array of other clothing, then encouraged to show his ‘red
shirt’ to his sister by saying ‘‘Look! My red shirt!,’’ being prompted as necessary.
– supported joint activities help to expand children’s reciprocity, communication,
social, and play skills as well as it also helps to increase age appropriate cognitive,
motor, and adaptive skills

45. Examples of NDBI
■ Early Start Denver Model (ESDM; Dawson et al. 2010; Dawson et al. 2012; Rogers and
Dawson 2010; Rogers et al. 2012),
■ Reciprocal imitation training (RIT; Ingersoll 2010; Ingersoll and Schreibman 2006),
■ Project ImPACT (Improving Parents As CommunicationTeachers (Ingersoll andWainer
2013a, b),
■ JointAttention Symbolic Play Engagement and Regulation (JASPER; Kaale et al. 2012,
2014; Kasari et al. 2006, 2008, 2010, 2014a, b),
■ SocialCommunication/Emotional Regulation/Transactional Support (SCERTS; Prizant
et al. 2003) and Early Achievements (Landa et al. 2011; Landa and Kalb 2012)

46. TREATMENT
Miscellaneous

47. Miscellaneous
■ MusicTherapy
– Given their universal appeal, intrinsic reward value and ability to modify brain and
behaviour, musical activities have been proposed as a potential strength-based
rehabilitation tool for ASD.
– In a trial, it has been demonstrated that 8–12 weeks of music intervention can
indeed alter intrinsic brain connectivity and improve parent-reported outcomes in
social communication in school-age children with ASD.

48. Take Home Message
■ There has been shift in the ICD 11 guidelines to make it more compatible with DSM-5.
■ New researches are being focussed towards discovering drugs that improve social
functioning of the individuals.
■ New behavioural techniques are aimed at not just improving skill in a particular field
but putting use of that skill to improve functionality in other areas as well.

49. References
■ Pellissier LP, Gandía J, LabouteT, Becker JAJ, Le Merrer J. μ opioid receptor, social
behaviour and autism spectrum disorder: reward matters. BrJ Pharmacol.
2018;175(14):2750-2769. doi:10.1111/bph.13808
■ Zhou J., Blundell J., Ogawa S., et al. Pharmacological inhibition of mTORC1 suppresses
anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice. J.
Neurosci. 2009;29:1773–1783
■ Krueger D.A., Care M.M., Holland K., et al. Everolimus for subependymal giant-cell
astrocytomas in tuberous sclerosis. N. Engl. J. Med. 2010;363:1801–1811
■ Lee H.J., Macbeth A.H., Pagani J.H.,YoungW.S., 3rd Oxytocin:The great facilitator of
life. Prog. Neurobiol. 2009;8:127–151. doi: 10.1016/j.pneurobio.2009.04.001.
■ Sharda M,Tuerk C, Chowdhury R, et al. Music improves social communication and
auditory-motor connectivity in children with autism. Transl Psychiatry. 2018;8(1):231.
Published 2018 Oct 23. doi:10.1038/s41398-018-0287-3

50. References
■ Profound impairment in social recognition and reduction in anxiety-like behavior in
vasopressinV1a receptor knockout mice.Bielsky IF, Hu SB, Szegda KL,Westphal H,
Young LJ
■ Neuropsychopharmacology. 2004 Mar; 29(3):483-93.
■ Oxytocin in the medial amygdala is essential for social recognition in the
mouse.Ferguson JN, AldagJM, InselTR,Young LJJ Neurosci. 2001 Oct 15; 21(20):8278-85.
■ Oxytocin, vasopressin, and social recognition in mammals.Bielsky IF,Young LJ Peptides.
2004 Sep; 25(9):1565-74.

51. References
■ Hardan A., Parker K., Garner J. A Randomized ControlledTrial of IntranasalVasopressin
Treatment for Social Deficits inChildren with Autism. 4th ed.World Summit of
Pediatrics; Rome, Italy: 2018.
■ Bolognani F, delValle Rubido M, Squassante L,Wandel C, Derks M, Murtagh L et al.A
phase 2 clinical trial of a vasopressinV1a receptor antagonist shows improved adaptive
behaviors in men with autism spectrum disorder. ScienceTranslational Medicine.
2019;11(491):eaat7838.
■ Tavassoli,T., Miller, L. J., Schoen, S.A., Nielsen, D. M. & Baron-Cohen, S. Sensory over-
responsivity in adults with autism spectrum conditions. Autism 18, 428–432 (2014).

52. References
■ Zhang L, Huang C, DaiY, Luo Q, JiY,Wang K et al. Symptom improvement in children with
autism spectrum disorder following bumetanide administration is associated with
decreased GABA/glutamate ratios.Translational Psychiatry. 2020;10(1).
■ Chawarska K, Macari S, Shic F. Decreased spontaneous attention to social scenes in 6-
month-old infants later diagnosed with autism spectrum disorders. Biol
Psychiatry 74(3):195-203, 2013
■ Jones,W., & Klin, A. (2013). Attention to eyes is present but in decline in 2-6-month-old
infants later diagnosed with autism. Nature, 504(7480), 427–431.
https://doi.org/10.1038/nature12715
■ Flanagan JE, Landa R, Bhat A, Bauman M. Head lag in infants at risk for autism: a
preliminary study. Am J OccupTher. 2012;66(5):577-585. doi:10.5014/ajot.2012.004192

53. THANKYOU