Pharmacological treatments for ASD: Research Initiatives
Transcript of Pharmacological treatments for ASD: Research Initiatives
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Unpublished 2012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