Lecture 4: ADHD and Autism

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Attention Deficit Hyperactivity Disorder (ADHD)
Inattention
Hyperactivity
Impulsivity
Prevalence is greater in males than females (10% vs 3%)
1 in 20 people have ADHD, AIHW survey 7% in <adult
Hyperactivity risk at 15% in indigenous compared to 10% in non-indigenous
Difficult to complete tasks - easily distracted
Clumsy (due to impulsivity and motor dysfunction)
Can be aggressive and hyperaroused
Attention Deficit Hyperactivity Disorder (ADHD)
May subside in adulthood, improvement linked to maturation of PFC - usually still evidence of disorder in ¾ as adults
Poor relationship with others, occupational dysfunction
Anxiety disorders, low self esteem
Predisposed to drug use?
65 % of cases genetic (inherited) – hyperactive-impulsive
70 % of cases genetic - attention deficit
Catecholamine hypothesis
ADHD
Mesocorticolimbic Dopamine
Mesostriatal Dopamine
VTA = ventral tegmental area (A10 dopamine)
Mesocorticolimbic Dopamine
Mesostriatal Dopamine

D1 and D2 receptors
Striatum = fine motor control
Prefrontal cortex = attention
Nucleus accumbens = reward
Attention Deficit Hyperactivity Disorder (ADHD)
Nucleus accumbens & VTA = impulsive/hyperactive
Striatum = fine motor inhibition - clumsy
Prefrontal cortex = poor attention-related processing
Dopamine involved
ADHD: Noradrenaline is also involved
Locus coeruleus releases noradrenaline which impacts on prefrontal cortex and attention
Alpha and beta receptors
ADHD: Noradrenaline and Dopamine
Noradrenaline & dopamine control glutamate and GABA neurons in their terminal areas
ADHD - the signal from noradrenaline and dopamine is ‘noisy’
Control of the prefrontal cortex and nucleus accumbens is erratic in ADHD
ADHD: Noradrenaline and Dopamine
Neurons produce LESS dopamine or noradrenaline (also evidence that amount of dopamine transporters is increased - greater uptake)
Per action potential, less neurotransmitter is released/has time to act at receptors
To compensate, the neuron needs to fire at a higher frequency
Leads to a noisy erratic signal, reducing the ability for the neurons to communicate effectively
ADHD: Treatment
Treatment for ADHD is aimed at reducing the ‘noise’ and high firing frequency
Treatments enhance the amount of time that dopamine or noradrenaline is in the synaptic cleft
Increases neurotransmitter amount
Decreases frequency of firing
The ‘signal’ is clarified
Noradrenaline and dopamine can remain in control!
ADHD: Treatment: dopamine (DA) vs (NA)
Aim at increasing dopamine or noradrenaline or both: HOW?
Reuptake (Transporter) Antagonists
Methylphenidate (Ritalin 10, Ritalin LA, Attenta, Concerta, Artige)
Atomoxetine (Strattera)
Dexamphetamine, Lisdexamphetamine (Aspen, Vyvanse, less prescribed - addictive/stimulant)
Tricyclic antidepressants (used to be used - not safe in kids)
Normal Transporter Activity
normal reuptake of dopamine and noradrenaline
Reuptake (Transporter) Blockers
Blocks dopamine transporters - helps with ADHD symptoms
Reuptake (Transporter) Blockers for ADHD
Methylphenidate (Ritalin, Attenta, Concerta)
Dopamine and Noradrenaline Transporter Blockers (reuptake inhibitors)
Extended-release methylphenidate (Ritalin LA)
OROS methylphenidate (Concerta)
Atomoxetine (Strattera) - was called tomoxetine
Reuptake (Transporter) Reversers for ADHD
Dexamphetamine, Lisdexamphetamine (Aspen, Vyvanse)
Other Therapies for ADHD
Guanfacine (Intuniv), Clonidine (Catapres) – alpha 2 (A2) receptor agonist
Antipsychotics
Quetiapine (Seroquel) and Risperidone (Risperdal)
Reuptake (Transporter) Blockers for ADHD
Methylphenidate (Ritalin, Attenta, Concerta)
Dopamine and Noradrenaline Transporter Blockers (reuptake inhibitors)
Needs to be administered at least twice daily
Reuptake (Transporter) Blockers for ADHD
Methylphenidate (Ritalin, Attenta, Concerta)
Extended-release methylphenidate (Ritalin LA)
Bimodal capsule - has both fast acting immediate release beads and enteric coated (avail in 4 hrs)
Offset of treatment less pronounced: less rebound effect
Side effects: nervousness, insomnia, decreased appetite
Reuptake (Transporter) Blockers for ADHD
Methylphenidate (Ritalin, Attenta, Concerta)
OROS methylphenidate (Concerta)
12 hour therapeutic effect
Outer coating of immediate release methylphenidate (22%)
Remainder released by osmotic pump delivery (OROS)
Better at maintaining a stable amount of drug
Reuptake (Transporter) Blockers for ADHD
Atomoxetine (Strattera) - was called tomoxetine
Non-stimulant (initially manufactured as antidepressant)
Selective for Noradrenaline Transporters
Directed at attentional processes
Half-life 5 hours (methylphenidate only 2.4 hr in kids)
Side effects: abdominal pain, decreased appetite, irritability
Very important to monitor cardiovascular system (noradrenergic)
Potential for abuse?
Reuptake (Transporter) Reversers
Dexamphetamine, Lisdexamphetamine (Aspen, Vyvanse)
Stimulant with less efficacy
Blocks DAT and NET by reversing their function (stops uptake and also increases release of catecholamines via the transporter)
Half-life: D-amphet 9 hours, L-amphet 11 hr in kids, taken every 4-6 hours (immediate release tabs) or daily am (extended release tabs)
Side effects: increased blood pressure, decreased appetite, irritability, insomnia
Potential for abuse?
Other Therapies for ADHD
Guanfacine (Intuniv), Clonidine (Catapres) – alpha 2 (A2) receptor agonist
Can be used as adjunct therapy or second line treatment
Agonists at A2 receptors activates NA neurons of LC (increasing NA release in PFC) and directly acts on A2 receptors in PFC (postsynaptic on pyramidal neurons)
Both mechanisms help to regulate attention and behaviour
A2 receptor activation for sympathetic nervous system causes vasodilation and reduced blood pressure (calming effect?).
Other Therapies for ADHD
Antipsychotics
Quetiapine (Seroquel) and Risperidone (Risperdal) can be used at low doses to offset side effects of re-uptake blockers, or reduce aggression/anger
ADHD Summary
ADHD is a paediatric disorder that is increasingly persisting into adulthood
Abnormalities in dopamine and noradrenaline signalling underpin the disorder (PFC)
Drug treatments are aimed at normalizing catecholamine signalling (transporter blockers & reversers, A2 agonists)
Antipsychotics may also be used as adjunct therapy
Autism Spectrum Disorder (ASD)
Developmental abnormalities in
Social interaction/communication
Motor ability/co-ordination
Sensory systems
Speech
Language
Attention
Lack of imagination
Usually develops by 1.5-3 years
more in males than females
Similar prevalence between nonindigenous and indigenous populations
Shares 28% comorbidity with ADHD
Case Study: Autism Spectrum Disorder (ASD)
Anna 4 years old
Poor eye contact
Disregarded people
Too attached to mother
Inconsistent response to verbal stimuli
Solitary play
Echolalic (repetitive sounds)
Unable to initiate or engage in conversation
Lined up toys, flicks light switch on and off
Hand flapping
Covers ears when upset
Acute episodes of agitation and aggression
Neuropathology of ASD
Shorter cerebellum
Alterations in prefrontal cortex and medial temporal lobe
Increased density of (smaller) neurons in:
Amygdala
Cortex (entorhinal)
Hippocampus
Many regions implicated, particularly frontal and subcortical – heterogeneity as with ASD
Thought of as a genetic disorder: 96 % concordance in monozygotic twins Role for epigenetic factors?
Epigenetics of ASD
Epigenetics: molecular changes that regulate expression of genome
Histones=basic & positively charged proteins that interact and bind with the acid and negatively charged DNA molecule.
Chemical modifications that change the charge of the histone protein will change how tightly it associates with DNA and vice versa
Methylation of histones can either increase or decrease gene transcription depending on where it occurs
Methylation of the DNA molecule usually silences gene transcription
400 differentially methylated genes detected in placenta of children later diagnosed with ASD
Other Causes of ASD?
Phenylketonuria
Mother contracts measles/influenza while pregnant (repeated exposure)
Hormone abnormalities of mother during pregnancy
Thalidomide - anti-nausea medication in pregnancy
Opioid excess theory
High 5-HT during development (Hyperserotonaemia)
Little evidence that MMR vaccination of mums2b, or children causes autism
Phenylketonuria (PKU)
Inability to break phenylalanine down to tyrosine (to then make dopamine)
Ingestion of phenylalanine increases brain levels
Phenylalanine inhibits myelination of neurons
Can result in autistic disorder, learning disorders or psychosocial problems
Opioid Excess Theory
Leaky stomach lining
Increased absorption of peptides such as gluten (wheats) and casein (dairy)
Gluten and casein cross BBB
Gluten and casein act like opiates when not fully metabolised
Activate opiate receptors similar to addictive opiates
Craving for foods containing gluten and casein
Serotonergic Dysfunction in ASD
Increased serotonin in periphery (Hyperserotonaemia) - 30% of children with ASD
Crosses to brain easily in developing brain (BBB not complete until 2 yo)
High levels cause negative feedback (5HT1A) on serotonin cells and loss of terminals
Serotonin in babies is required for development of synapses, dendrites
Serotonin enhances oxytocin (bonding neurotransmitter) release
Reduced brain serotonin impacts on normal development - autistic disorder
Treatments for ASD
Behavioural therapy
Dietary constraints (no wheat or dairy, food additives)
Pharmacotherapies treat the symptoms not the core aspects of ASD
Anxiety, Obsessive behaviour: SSRI antidepressants
Aggression: Atypical antipsychotics
Hyperactivity: stimulants used for ADHD
Tics: A2 agonists (clonidine), antipsychotics
Seizures: Anticonvulsants
Sleep difficulties: Melatonin (Slenyto)
ASD Summary
Autism is an understudied developmental disorder
Current research indicates the involvement of many brain regions
Behavioural therapy is most effective treatment at present
Diet is also important
Pharmacotherapies treat related symptoms