Pharmacological treatments for ASD: Research Initiatives

Royal College of Psychiatrists London 2021

Gráinne McAlonan

Professor of Translational Neuroscience

Institute of Psychiatry, Psychology and Neuroscience

King’s College London

DisclosureResults of an Investigator Initiated study of cannabidiol in ASD funded by GW Pharmaceuticals will be presented. The funder had no role in the conduct of the study, the analyses, or the decision to publish.

SSRIs

SSRI Age (years)

Sample size Drug and Dose (final mean)

Duration (weeks)

Outcome

Barthelemy et al., 1989

3-10 13 Fenfluramine1.5mg/kg

12 No change

King et al., 2009 5-17 149 Citalopram16.5mg/day

12 GCI-INo change

Hollander et al., 2005

5-17 45 Fluoxetine10mg/day

16 CYBOCS

Unpublished 2012

5-17 158 Fluoxetine2-18mg/day

14 CYBOCSNo change

McDougle et al., 1996

18-53 30 Fluvoxamine 12 CYBOCS

Buchsbaum et al., 2001

30 6 Fluoxetine20-40mg/day

16 CYBOCSHam-Anxiety

Hollander et al., 2012

18-60 37 Fluoxetine20-40mg/day

16 Y-BOCS

Side effects of Citalopram in children

• incr energy

• impulsiveness

• decr concentration

• hyperactivity

• incr stereotypy

• diarrhoea

• initial insomnia

• dry skin

• x1 seizure

SSRIs in Clinical Trials

Children – NOT SUPPORTED

Children - Side effects – NOT RECOMMENDED

Adults - Some evidence

e.g. fluoxetine for repetitive/restrictive behaviours

Benefits of very low dose fluoxetine in children with autism spectrum disorders.Crowell et al., JAACAP S166 2017

CHILDREN (N=14) RESPONDED VERY WELL

REDUCTION IN IRRITABILITY AND REPETITIVE BEHAVIOURS

DOSES 2MG-5MG STARTING (FINAL DOSE 2-15MG)

IMPROVEMENT WITHIN A FEW DAYS

SUGGESTS A DIFFERENT MECHANISM?

Dopamine blockers

Dopamine block

Age(weeks)

Sample size Drug and Dose(final mean)

Duration Outcome

McDougleet al., 2005

8 101 Risperidone2mg/day

8 or 16 Y-BOCSVABS

Scahill et al., 2013

4-17 225 Risperidone0.5-3.5mg/day

8 ABC-L/SW

Marcus et al., 2009

6-17 218 Aripiprazole5, 10 or 15mg/day

8 ABC-I

Owen et al., 2009

6-17 98 Aripiprazole5, 10 or 15mg/day

8 ABC-I

Aman et al., 2010

6-17 316 Aripiprazole5, 10 or 15mg/day

8 ABC-I

Antipsychotics for children without psychotic disorder; 2018

• 5-24 years

• Controls n = 189,361

• Antipsychotics n = 58,497

• Risk of death x3.5

• From cardiovascular or metabolic causes x4.3

• Relatively low suicidality

Dopamine blockers

SOME BENEFIT FOR REPETITIVE BEHAVIOURS

BUT PATIENTS SELECTED ON BASIS OF HIGH

IRRITABILITY

POTENTIAL RISK OF ADVERSE SIDE EFFECTS

LOW DOSE TO START

Identifying intervention targets for ASD

Looking at brain response:Shiftability studies in ASD

oSingle dose challenge methodology

oTo identify new targets

oAnd target engagement

oRecognising neurochemical heterogeneity

oGenerating a repertoire of pharmacological options which can be tailored to individuals/subgroups

Hranilovic et al. (2007).

Wichers, R. et. al. 2020 in revision Molecular Autism

Autistic differences in brain function

Respond to single dose of

Tianeptine

Stahl CNS Spectrums, 2015

Progress toward treatments for synaptic defects in autismDelorme, et al., Nature Medicine 19,685–694(2013)

Riluzole

Contr

ol

ASD

-0.04

-0.02

0.00

0.02

0.04

0.06

D In

hib

ito

ry In

dex (

GA

BA

/(G

AB

A+

Glx

)

*

Riluzole shifts E-I (GABA)

Ajram et al., Trans Psych 2017

Ajram et al., Trans Psych 2017

Pilot results (INSAR 2017)A Randomized Controlled Trial of Riluzole in Autism Spectrum Disorder

Thursday, May 11, 2017: 2:40 PM

R. Nicolson et al.

Conclusions: Although riluzole was generally well-tolerated, it was not superior to placebo in terms of reduction in the core symptom domains of ASD. However, patients taking riluzole did show a significantly greater reduction in hyperactivity and irritability, both of which are interfering symptoms commonly associated with ASD.

Autistic differences in sensory (visual) processing

Depend upon GABA

Huang, Pereira et al., 2020 in submission

GABA is a target (for sensory differences)

Visual processing differences in ASC respond to a single dose of

arbaclofen

Huang, Pereira et al., 2020 in submission

Control group ASC group

Arbaclofen in Clinical Trial

/

The autistic brain is pharmacologically atypical

Biology can be shifted in ASD, even in adults.

Responsivity to 5HT and E-I challenge is

different in autistic and neurotypical adults.

CBD modulates glutamate, GABA and 5HT

Agonism at the Transient Receptor Potential Vanilloid type 1 (TRPV1) receptor ◦ incr Glu and GABA

Antagonism at the G protein-coupled receptor 55 (GPR55), especially in the basal ganglia◦ increase GABA transmission

Agonist at prefrontal 5-HT1A receptors (prefrontal cortex), ◦ suppresses glutamate and GABA signalling.

eCB gene variants linked to social function

eCB gene anomalies have been reported in ASD

Lower levels of circulating eCBs observed in ASD

CBD limits seizures and ameliorates social deficits in a mouse model of Dravet syndrome

Efficacy of CBD reported in ◦ epilepsy

◦ social phobia

◦ social anxiety

◦ ADHD

◦ schizophrenia Karhson et al. Transl Psychiatry. 2016; Bhismadev et al. Neurotherapeutics. 2015; Aran et al. Mol Autism; Bakas et al. Pharmacological Research 2017; Lowin t, Straub RH Arthritis Res Ther. 2015; Whalley Bet al. Neurology. 2018; Russo et al. Neurochem Res. 2005; Kaplan et al. Proc Natl Acad Sci U S A. 2017; Bergamaschi et al. Neuropsychopharmacology. 2011; Cooper et al. Eur Neuropsychopharmacol. 2017; Campbell et al. J Pediatr Pharmacol Ther. 2017; Devinsky et al. Lancet Neurol. 2016; Devinsky et al. N Engl J Med. 2017; Thiele et al. Lancet. 2018; McGuire et al. Am J Psychiatry. 2018

Whole group effect of drug (CBD>PLC)

ASD effect of drug in R fusiform face area (CBD>PLC)

ASD effect of drug in Cerebellum (CBD>PLC)

Pretzsch et al., J Psychopharm 2019

Summary

Biology can be shifted in ASD, even in adults.

Pharmacological responsivity is different in

adults with ASD

5HT modulates brain function differently in ASD

The responsivity of the GABA-glutamate system is

altered in ASD

GABA control of sensory function is altered in ASD

Cannabinoids (polypharmacy) shift brain

function

Clinical trials now underway across the

lifespan to boost repertoire of options for

ASD

Nichol Wong Francesca Ponteduro

Hester Velthius Andreia Pereira Charlotte Pretzsch

Thanks to the ‘shiftability’ team, our funders and all our participants

Collaborating P.I.s:

Prof Declan Murphy

Prof Steve Williams

Dr Eileen Daly

Laura Ajram

James Findon Rob Wichers