ADHD

Question 1

Aetiology

Answer 1

There is a 70-90% heritability in twins and 5x increased risk if a first degree relative has it → among the most heritable psychological disorders.
Environmental factors include neonatal hypoxia, maternal smoking/alcohol use, and premature birth and low birth weight.
Prevalence also increased with social deprivation, learning disability, institutional rearing and incidence of other brain diseases or neurological disorders (e.g. epilepsy).
Neurobiology - smaller and less active fronto-striatal complex with reduced striatal metabolism - MRI and PET evidence.
Hyperactive sensory cortex seen in PET scans → enhanced perception of environmental stimuli such as light and sound.

Question 2

Comorbidities

Answer 2

Oppositional defiant disorder (ODD) - 40%
Anxiety disorders - 34%
Conduct disorder - 14%
Tics - 11%
Mood disorders - 4%

Only 31% of patients have JUST ADHD.

Question 3

Neuroanatomy

Answer 3

4% reduction in brain size with a 8% decrease in the frontal lobe → affects problem solving, spontaneity, memory, language, irritations, judgement, impulse control and social behaviour.
- the dorsolateral cortex involved in decision making, mood regulation and conflict management is particularly affected.
- smaller and less active fronto-striatal lobe seen in MRI
Reduced striatal metabolism seen in PET → striatum controls aspects of cognition and social behaviour
Basal ganglia is 6% smaller in children, but this is normalised around the age of 18
Cerebellum is 12% smaller, and this becomes more pronounced around the age of 18.

Question 4

Genetics

Answer 4

Twin studies show 80% heritability - very high.
Primary candidate genes for ADHD are linked to dopaminergic or serotonergic neurotransmission, e.g. DAT, D4 and D5 receptors, SERT, 5-HT1B receptors.
The D4 receptor prevalent in fronto-cortical networks has a high-risk 48 base pair repeat that results in attenuated cAMP responses to dopamine and adenylyl cyclase coupling to the receptor. High correlation with ADHD, particularly with inattention symptoms.
The DAT1 gene has a high-risk 480 base pair repeat associated with elevated striatal DAT expression and therefore reduced synaptic dopamine.
Other genes involved include the A1 allele of the dopamine D2 receptor.
marginal linkage dopamine D5 receptor gene polymorphisms in TMR
Dopamine neurotransmission is hypofunctional in ADHD, particularly in fronto-striatal areas.

Question 5

Methylpenidate

Answer 5

Striatal DAT levels are increased in ADHD.
This is reduced after 4 weeks of methylphenidate treatment, which binds to the DAT transporter.
Ventral striatal DAT elevates after 12 months of treatment (compensatory increase), showing neuroplasticity which could decrease treatment efficacy with long-term treatment.
Short-term treatment seems to be effective, but the opposite of the desired effect occurs with long-term treatment.

Question 6

Dopamine neurotransmission

Answer 6

Hypodopaminergic signalling, particularly in fronto-striatal areas
Associated with increased DAT expression in the striatum and mutations in D4, D2 and D5 receptors.

Question 7

Glutamatergic signalling

Answer 7

Glutamate signalling is interconnected with dopaminergic signalling.
Glutamatergic signalling plays a role in ADHD susceptibility, attention impairment and hyper-impulsive symptoms.
There is hyperglutamatergic signalling
Ionotropic - GluN2A and GluN2B subtypes of NMDA receptors are strongly involved.
Metabotropic - Gq-coupled mGluR5

Question 8

Interactions between Glutamate and Dopamine signalling

Answer 8

Stimulation of D2 causes inhibition of NMDA receptors.
Stimulation of D4 decreases AMPA expression at the synapse and so reduces PFC pyramidal neuron excitation.
Striatal glutamate release facilitates dopamine release by acting on NMDA receptors.
AMPA GluA1 KO mice and GluA3 deficient mice display elevated dopamine concentrations in the striatum.

Hypodopaminergic state in ADHD leads to more active NMDA and AMPA receptors, causing hyperglutamatergic activity and signalling dysfunctions.

Question 9

Psychostimulants - bind DAT

Answer 9

Methylphenidate, and the slow-release preparations Equasym and Concerta XL, inhibit DAT and NAT.
Dexamphetamine - Dexedrine and Adderall
Lis-dexamphetamine - Vyvanse- pro-drug.

Question 10

Non-stimulants - NAT inhibitors

Answer 10

Atomoxetine (Strattera) - slow onset, may cause less addiction

Question 11

Glutamatergic targets

Answer 11

Memantine - NMDA receptor antagonist
Fasoracetam - nonselective mGluR activator

Question 12

Other treatments

Answer 12

Clonidine and Guanfacine – α2 adrenoceptor agonists
Tricyclic antidepressants (desipramine, imipramine) – NAT inhibitors, also affect serotonin, histamine and ACh transmission