ADHD (finished) Flashcards
What is the DSM-V criteria for ADHD?
- > 6 inattention and/or hyperactivity/impulsivity features for 6 months before age 12 (>5 in adults)
- Symptoms present in at least 2 life areas: school, home, work or social setting
- Defining criteria are developmentally inappropriate behaviours (age 4 vs age 12)
What are the 2 categories that ADHD symptoms are categorised by?
- Inattention
- Hyperactivity/impulsivity
List some of the behaviours that come under inattention in ADHD:
- Lack of attention to detail
- Difficulty to sustain attention
- Does not listen
- Not follow thru instructions
- Difficulty organising tasks
- Avoid sustained attention
- Lose or misplace objects
- Easily distracted
- Forgetful
List some of the behaviours that come under hyperactivity/impulsivity in ADHD:
- Fidgeting
- Restless during activities
- Running about
- Excessively loud
- Always “on the go”
- Talks excessively
- Blurts out answers
- Interrupt or intrudes upon others
How many prison inmates are estimated to suffer from ADHD, why does this link?
Up to 20% of inmates suffer from ADHD
Ppl who suffer from ADHD are stuck in the present (consumed by the experience) –> so cannot see the concequences of their actions
What is the aetiology of ADHD?
- Genetic & environmental
- 70-90% heritability in twins
- 5x increase risk in first degree relative
What are the main environmental factors of ADHD?
- Neonatal hypoxia
- Maternal smoking
- Premature birth
What is the neurobiology of ADHD?
- MRI = smaller less active front-striatal complex
- PET = reduced striatal metabolism
- Hyperactive sensory cortex (easily enhanced by any little stimulus)
What is the prevalence of ADHD?
- ADHD (DSM-V) = 3-5%
- USA defining = 0.5-1.5% (hyperkinetic disorder)
- Boys > Girls 2:1
List 6 specific environmental factors that are associated w increased prevalence:
- Extreme prematurity & low birth weight
- Maternal smoking / alcohol
- Low social class grp / social deprivation
- Learning disability
- Institutional rearing
- Other brain diseases / neurologicla disorders (e.g. epilepsy)
How does ADHD affect someone over their lifetime?
How prevalent is ADHD alone & why?
- Has a 31% prevalence
- ADHD has a high co-morbidity so occurs alone less often than not
What are some disorders that ADHD is often co-morbid with?
- Oppositional defiant disorder (ODD) = 40%
- Anxiety disorder = 34%
- Conduct disorder = 14%
- Tics = 11%
- Mood disorders = 4%
(Co-morbid disorders may req their own theraputic intervention)
What are the changes that occur in the brain in ADHD?
- Smaller brian (~4%) –> right frontal lobe (~8%)
- Smaller basal ganglia (~6%) –> normalisation (~18 yrs)
- Smaller cerebellum (~12%) –> more pronounced (~18 yrs)
What are the volumetric differences in ADHD like?
- Manifest early (~6 years)
- Correlate with ADHD severity
- Are irrespective of medication status
- Are irresponsive of co-morbidities
What are the 2 key brain areas that are involved in ADHD?
Prefrontal cortex
Striatum
What is the role of the prefrontal cortex?
Decision making, mood regulation, conflict management
What is the role of the striatum?
Controls aspects of cognition & social behaviour
What is the aeitology of ADHD?
Environmental & genetic
What is the genetic risk of ADHD?
- 70-90% heritability in twins
- 5x increase risk in first degree relative
(Among the most heritable of psychological disorders)
What are the 6 genes that are linked to ADHD?
- SLC6A3
- DRD4
- DRD5
- SLC6A4
- HTR1B
- SNAP25
What are the proteins coded by each of these genes that are linked to ADHD:
- SLC6A3
- DRD4
- DRD5
- SLC6A4
- HTR1B
- SNAP25
- SLC6A3 = DAT
- DRD4 = D4 receptor
- DRD5 = D5 receptor
- SLC6A4 = SER-T
- HTR1B = 5-HT1B receptor
- SNAP25 = vesicle protein
What do most of the genes that are linked to ADHD cause?
Candidate genes are linked to dopaminergic or serotonergic neurotransmission
Why are the 6 genes linked & not causal for ADHD?
They have low odds ratios (relative risk)
No single gene is sufficient or causal (multiple genes w low risk)- combinations of mutant genes along with environmental impacts leads to more likely to develop several traits of ADHD
-
Give an example how one gene mutation is linked to a phenotypic trait in ADHD
Each gene may code a specific phenotypic trait- Dopamine D4 receptor (DRD4) linked to novelty seeking behaviour
What is odds ratio?
Odd ratios = chances that mutations in these genes are related to ADHD
Odds ratio of 1 = no association
What are the 2 main candidate genes in ADHD?
- D4 (Dopamine D4 recpetor) gene 11p15.3
- DAT1 (Dopamine transporter 1) gene 5p15.3
Where are D4 genes mainly expressed?
In cortical area networks
(Repressed cAMP response)
How does DAT4 gene affect ADHD?
Means there is more DAT expressed –> more transmitters = less dopamine in synaptic cleft
5 points about D4 gene causing ADHD:
- 7Repeat allele: Pooled Odds Ratio = 1.9 (1.4-2.2)
- Prevalent in frontal-cortical networks
- High risk allele: 48 bp repeat
- Results in an attenuated (weakened) cAMP response to dopamine
- May correlate w symptoms of innatention
4 points about DAT1 gene causing ADHD:
- Pooled Odds Ratio = 1.16
- Site of action = stimulant drug & elevated in ADHD
- High risk allele = 480 bp repeat
- May affect striatal DAT expression?
How do DAT levles change in ADHD pateints?
They have significantly increased DAT levels
(Inc striatal binding)
How can inc DAT levels in ADHD patients be treated?
Methylphenidate
= increased striatal binding to DAT is reduced following FOUR weeks of treatment using this
(Fixes amt of dopamine in synaptic cleft & treats the patient in the short term)
Although methlphenidate decreased DAT binding in the short term what happens with prolonged use?
Ventral striatal DAT is ELEVATED 12 months after use
Shows neuroplasticity which could decrease treatment efficacy
How does short vs long exposure to methylphenidate affect DAT levels?
Short = reduced DAT binding in striatum
Long = may increase DAT striatal binding –> a compensatory increase
What are the 2 environmental factors with the strongest association to ADHD?
- Extreme prematurity & low birth weight
- Intrauterine exposure to nicotine (or alcohol - FAS)
List all the environmental factors linked to ADHD:
- Extreme prematurity & low birth weight
- Intrauterine exposure to nicotine (or alcohol - FAS)
- Neonatal hypoxia
- Lead exposure
- Acquired brain disorders (e.g. encephalitis, brain trauma)
- Food allergies (i.e. sugars??) - no causal convincing evidence - no guidelines
What are the top 3 environmental/genetic factors for ADHD?
- Prematurity
- Low birth weight
- Maternal smoking
(Not genes! Environmental facotrs have a much higher Odds Ratio so are the strognest 3 factors)
What do gene polymorphisms & early life adversity (environmental) combine to cause?
Fronto-striatal monoamine dysfunction
This causes:
Devleopmentally inappropriate hyperactive, impulsive, inattentive behaviour
=
ADHD
Describe the neurobiology ADHD:
- Fronto-striatal dopaminergic (DAergic) hypo-function
- Higher density of dopamine transporter (DAT) in striatum
Describe the molecular genetics of ADHD:
- 7 repeat form od dopamine D4 receptor linked novelty
- 480 bp repeat (x10) of dopmaine transporter (DAT) associated ADHD
- Marginal linkage dopamine D5 recpetor gene polymorphisms in TMR
Where do dopminergic neurones mainly originate from & project to?
Originates = midbrain (ventral tegmental & substantia nigra)
Projects to = striatum & nucleus accumbens + prefrontal cortex
Where does glutamate originate from?
In Glial cells- Glutamate from glucose during the Krebs cycle and is converted into glutamine by glutamine synthetase
How does glutamine enter the presynaptic terminal?
Produced by glial cells
Transmits to presynaptic neuron via glutamine transporter
Glutamine is then oxidized back to glutamate and packed into vesicles by vGLUT
What are the 3 ionotropic glutamatergic synaptic subgroups in ADHD?
- GluN2A
- GluN2B
- GluK2
What role do the 3 ionotropic glutamatergic synaptic sub-groups have in ADHD?
- Role in ADHD susceptibility & attentional impairment in ADHD patients
- Hyperactive-impulsive symptoms
What are the 2 metabotropic glutamatergic synaptic sub groups in ADHD?
- mGluR5
- mGluR7
(They use cAMP signalling –> mutation of these cause attention deficit)
Outline some interactions associated with glutamate and dopamine signalling
Glutamate receptors (especially iGluRs) and dopamine receptors interact in many ways:
- When dopamine receptor D2 is activated = inhibition of NMDARs (glutamate receptor)
- Activation of dopamine receptor D4 = reduces activity of AMPARs (glutamate receptor) on excitatory neurons in the prefrontal cortex
- Activation of D4 reduces presence of AMPARs at synapses
- Glutamate release in striatum enhances release of dopamine acting on NMDARs
outline when these interactions between glutamate and dopamine signalling were observed (in mice)
Mice lacking GluA1 (a subunit of AMPAR) or with deficient GluA3 (another subunit of AMPAR) show increased levels of dopamine in the striatum.
Overall, what do interactions between glutamate and dopamine signalling result in?
Hypo-dopaminergic state in the ADHD may be expected to lead to more active NMDARs/AMPARs and a subsequent increase in glutamate output = take home message
What are the 4 types of medications for ADHD?
Psychostimulants
Non-stimulants (sub-groups:)
- Recently liscenced treatments
- Glutamatergic targets
What action do Psychostimulants have?
Bind to DA-transporters (DAT)
Give examples of psychostimulants used to treat ADHD:
Mehtylphenidate - Ritalin tabelt
Equasym, Concerta XL slow release preperations - DAT & NAT inhibitors
Equasym, Concerta XL, slow release preparations - DAT & NET inhibitors
Dexamphetamine - Dexedrine & Adderall
Lis-dexamphetamine - Vyanse (prodrug to be converted in the body)
Give examples of Non-stimulant drugs used to treat ADHD:
Atomoxetine - Strattera (slow onset less addiction?) NAT inhibitor
What action do non-stimulant drugs used to treat ADHD have?
Noradrenaline uptake inhibitor
Give examples of recently licensed treatments for ADHD:
Clonidine & Guanfacine - aplha 2 adrenoceptor agonists
Tricyclic antidepressents (desipramine, imipramine) - NAT inhibitors
Give examples of glutamatergic targets treatments for ADHD:
Mematine - an NMDA recpetos antagonist, improve ADHD symptoms in patients
Fasoracetam - a nonselective mGluR activator, showed clinical improvement
What are the 2 main divisions of ADHD treament drugs?
- Stimulants
- Non-stimulants
What general action do stimulants vs non-stimulants have on ADHD?
Stimulants = bind to DAT transporter (amphetamines used)
Non-stimulants = Target noradrenaline uptake (more noradrenaline in synaptic cleft)
Name some drugs associated with the treatment of ADHD + what effect do they have
Differential Pharmacology of Drugs
Variety of drugs target different pathways and receptors
Some effects on dopamine some on noradrenaline to positively impact ADHD
Norepinephrine & dopamine are used to treat ADHD - what is the efficacy of these being used?
- Cognitive function ↑
- Attentiveness ↑
- Distractibility ↓
- Hyperactivity ↓
- Behavioural disruption ↓
Norepinephrine & dopamine are used to treat ADHD - what are the adverse effects of these being used?
- Insomnia ↑
- BP/HR ↑
- Nausea/vomiting ↑
- Abdominal pain ↑
- Tics ↑?
- Appetite ↓
- Bodyweight ↓
- Growth rate ↓
Describe the main way of action of the drugs used in the treatment of ADHD
How does medication work?
Dopamine transporter mutated in ADHD = less dopamine in synaptic cleft
Less receptor activity = less dopamine activity
Drugs block transporter = more dopamine in synaptic cleft that can target receptors
= MAIN CHARACTERITIC OF DRUGS
Describe the normal physiology of dopamine signalling (no drugs involved)
Dopamine in the synaptic cleft is reuptaken by pre-synaptic terminal and packed into vesicles by VMAT
Describe how methylphenidate works
Inhibits DAT transporter = more dopamine in synaptic cleft (less reuptaken)
- dependent on the firing rate
Describe how amphetamine works
Also inhibits DAT- but blocks differently at certain site = reduces uptake and more dopamine in synaptic cleft
Also get introduced into the neuron- so can now block the VMAT = more dopamine present in cytosol of neuron that can be released into synaptic cleft
- independent on the firing rate
Which has a stronger effect: methylphenidate or amphetamine
Amphetamine
Describe a study showing the effect of methylphenidate + the results
Study = methylphenidate given to patients + raclopride (= radio labelled compound that binds to DAT) = PET scan:
Normal patients = very strong signal in straitum as raclopride binds to DAT transporter
Treat patients with methylphenidate = blocks DAT transporter = more dopamine in synaptic cleft = more dopamine can bind to receptor and outcompete raclopride = reduced signal
Describe the outcomes of taking methylphenidate
Outcomes: both, stimulants and reward, enhance dopaminergic function
- Elevate DA in the ventral striatum
- Enhance DA and Nuc.accumbens in the frontal cortex.
- Increased frontocortical transmission reinforce executive function, focus attention and improve inhibition of impulsivity = IMPROVES ADHD symptoms
