Pharmacological treatments for ASD
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1 Behavioural and Developmental Psychiatry Clinical Academic Group (CAG) 18 June 2015 Pharmacological treatments for ASD Dr Grainne McAlonan Head of Research BDP CAG, King s Health Partners Reader (Clinical), Dept. of Forensic and Neurodevelopmental Sciences King s College London
2 Outline Barriers to treatment Current symptomatic treatments New approaches Glutamate/GABA and 5HT Treatment biomarkers Shifting BIOLOGY
3 Barriers to intervention in ASD ASD shows wide clinical diversity. Case identification is still solely clinical. Hence clinical trials involve biologically heterogeneous patients. Poor understanding of pathophysiology NO TREATMENT TARGETS NO agreed outcome measures (in childhood or adulthood) Especially measures which capture outcomes that matter to the individual and their families NO clinical trial networks
4 Autism Spectrum Disorders Autism Speaks Rob Ring
5 Medicines under investigation Arbaclofen Atomoxetine Aripiprazole N-acetyl-cysteine Citalopram Basiglurant Glutathione Riluzole Risperidone AVPR1A antagonis Oxytocin IGF-1 Loxapine Minocyclin Vitamin D Sulforophane Omega 3 Trichuris suis ova
6 Anti-epileptic medications 7 RCTs (total n = 171); three of valproate, and one each of lamotrigine, levetiracetam, and topiramate. Meta-analysis - no significant difference between medication and placebo; irritability/agitation; global improvement. Limitations lack of power different medications with diverse actions.» Hirota et al., J Autism Dev Disord (2014) 44:
7 Anti-psychotic medications Primarily studied for effects on challenging behaviours : irritability, self-injury; aggression Evidence of benefit, but studies are mainly in childhood cohorts. Adverse effects problematic McPheeters et al., 2011 Pediatrics
8
9 SSRIs SSRIs No evidence to support use in children with ASD; some support for use in adults. Williams, K., et al., Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD). The Cochrane Library, McPheeters et al., 2011 Pediatrics SSRI In adults, may improve compulsivity Hollander et al Am J Psych
10 ADHD and ASD Christakou, Murphy et al., 2013 Molecular Psychiatry DLPFC SMCx Cb Thal Prec
11 Stimulants for symptoms of ADHD in ASD Studies in children Stimulants first line, few RCTs, response rate 50%, higher rates of side effects. Mahajan et al., 2012 PEDIATRICS Volume 130
12 New Opportunities IDENTIFYING PHARMACOLOGICAL TARGETS IN ASD
13 Risk genes for ASD have been identified o Especially linked to synaptic function Key neurochemical / peptide /inflammatory pathways have been identified. o Glutamate-GABA o 5HT o Microglial activation o Oxytocin Can we identify more biologically homogeneous subgroups? Can we design targeted molecular/pharmacological treatment to those sub-groups? o Stratification pre Clinical Trial o Response prediction pre treatment
14 Progress toward treatments for synaptic defects in autism Delorme, et al., Nature Medicine 19, (2013)
15 Glutamate, GABA and EXCITATORY/INHIBITORY balance Magnetic Resonance Spectroscopy (MRS) can detect GABA and glutamate in vivo INHIBITORY INDEX = GABA/ (GABA + Glutamate) CAN WE SHIFT BIOLOGY? Riluzole (progaba/antiglu) drug challenge
16 Pilot study shifting excitatory/inhibitory balance with Riluzole. Adult males with and without ASD, aged No psychoactive medication on scan day 50mg oral riluzole or placebo 1 hour before scan Inhibitory Index measured in prefrontal lobe and subcortex. Manuscript in preparation
17 Riluzole in autism: Case studies All patients much improved or very much improved Wink et al., 2011; J Child Adol Psychopharm
18 GABA. A (very) pilot [11C]Ro positron emission tomography study A. nucleus accumbens B. amygdala C. hippocampus The brain GABA-benzodiazepine receptor alpha-5 subtype in ASD. Mendez et al, Neuropharmacology, 2013.
19 Next steps Does biological shift in response to Riluzole PREDICT subsequent treatment outcome?
20 5-HT in ASD BLOOD (Review McDougle 2005) Hyperserotonemia DECR 5-HT 2A receptor binding INCR 5-HT transporters and antibodies against brain 5-HT receptors GENETICS (Veenstra-VanderWeele and Cook 2004) Association with genes coding for 5-HT factors (eg: SLC6A4, HTR2A) NEUROIMAGING smri: 5-HTTLPR and gray matter volume (Wassink 2007) PET: 5-HT Metabolism (Chugani 1997, 1999) SPET: 5-HT 2A receptor binding (Murphy 2006) SYMPTOMS SSRIs treatment alleviates some symptoms (Review Kolevzon 2006) Acute Tryptophan Depletion leads to worsening of autistic symptoms (McDougle 1996)
21 5HT influences glutamate/gaba In development High 5-HT levels decrease the migratory speed of cortical glutamatergic and GABAergic neurons (Vitalis et al., Front. Cell. Neurosci., 2013; also Riccio et al., 2009, Mol. Psychiatry 14, , Transl. Psychiatry, 1:e47 Cirana Curr Pharm 4(2),
22 Acute Tryptophan Depletion to Decrease 5HT Biosynthesis of Serotonin from Tryptophan SHAM Drink: 16 Amino Acids ATD Drink: 15 Amino Acids (no L-Tryptophan) (Young 1989) ATD reduces blood tryptophan by 60-80% after 5-7 hours.
23 HAPPY Left Medial Frontal Gyrus BA9 Daly et al. Arch Gen Psychiatry
24 Pilot treatment studies targeting glutamate-gaba in ASD SSRI (Citalopram) v SSRE (Tianeptine) v Placebo Can we identify SUBGROUPS within the spectrum based on SSRI/SSRE response Does this PREDICT treatment outcome?
25 Academics, Clinicians, Research Staff and study volunteers: Acknowledgements The Behavioural Genetics Clinic, BDP CAG, King s Healthcare Partners Dept. of Forensic and Neurodevelopmental Disorders The BRC for Mental Health, Neurodevelopmental Disorders Theme Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience The Sackler Centre for Translational Neurodevelopment, Institute of Psychiatry
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