what do parents need to know about adhd medicines?
TRANSCRIPT
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What do parents need to know
about ADHD medicines?
Professor Peter Hill
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What you see
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emotional dysregulation
hyperactivity
personal disorganisation
inattention
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Is the result of problems in the
brain
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Frontal lobe in blue
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Some actions of the frontal lobe
• Impulse control
• Social judgement
• Executive functions: planning, self-
awareness
• Holding things in mind ‘working memory’
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Cortex is the dark purple outside
layer, full of nerve cells
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Brain problem 1
• Immature development and lower activity
of the frontal cortex
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Cortex development by age: check the
extent of dark colouration
Shaw 2007Replication Almeida 2010
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Delays in maturation of cortex: colours the other way round: dark is greater delay
Shaw P. et.al. PNAS 2007;104:19649-19654
© 2007 by The National Academy of Sciences of the USAOctober 14, 2019
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Less frontal lobe brain activity in ADHDNeurophysiology - blood flow SPECT
Frontal lobe
Cerebellum Sensory-motor cortex
Normal ADHD
Kuperman et al 1990
AetiologyAetiologyCase description ClassificationEmergence of a concept Comorbidity CostCore symtoms Epidemiology Implications
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Less brain activity on fMRI in
ADHD
Rubia
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Normal SPECT brain scan from below
Underside view
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SPECT: view from below
ADHD at rest ADHD concentrating
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Effect of stimulant medication
ADHD resting ADHD after stimulant
www.amenclinics.comOctober 14, 2019
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Brain problem 2
• Inefficient switching from ‘default mode’ to
‘task mode’
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Default mode network (purple/pink) vs Task
mode network (red/orange) in normal brain
Kelly 2008 Neuroimage 39:527-537
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In ADHD
• inefficient switching between default
(mind-wandering) mode and task mode
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Methylphenidate promotes task-
mode network: blue is active
ADHD
ADHD given methylphenidate
Normals
Liddle 2011 JCPP 52:761-771
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The point of ADHD medication
• To promote frontal lobe functioning
• In order to compensate for delayed
development and underactivity
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ADHD medication
• Makes nerve pathways in frontal lobe
cortex more effective
• by helping nerve cells pass messages
between themselves using
neurotransmitters
• usually by increasing the amount of
neurotransmitter available
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By increasing neurotransmitters at
the synapse between nerve cells
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The synapse
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Neurotransmitter 1: Dopamine and
noradrenaline
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Methylphenidate blocks the
dopamine transporter so that more
is available
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Methylphenidate and Dexamfetamine block
noradrenaline transporter and Dex displaces
noradrenaline and dopamine from vesicles
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Patients with ADHD respond differently to
Methylphenidate and Dexamfetamine• From a total of 174 ADHD patients participating in 6 crossover studies, 87% had
clinical response to stimulants when both amfetamine (AMF) or methylphenidate
(MPH) were tried1
• The overall response to MPH and AMF is similar, however the response to each
medication varies among individual patients2
1. Arnold LE. J Attent Disord 2000;3:200-11.2. Hodgkins P et al. Eur Child Adolesc Psychiatry 2012;21:477-92. Bob
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Ramdtvedt et al. (2013)
J Child Adolesc Psychopharmacol 23, 597-604.
72% respond to either MPH or DEX alone (equal proportions)
If trial both MPH and DEX, 92% have favourable response
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The vocabulary of prescribing: the
names of medicines
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Chemical2-piperidineacetic acid, α-phenyl-, methyl ester
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Scientific generic
methylphenidate
(mee thyle fenni date)
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Medicine name: brand
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Thus
• Chemical name
• Scientific generic name
• Brand name
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Brand names of methylphenidate in the
UK
• Medikinet
• Ritalin
• Tranquilyn
• Equasym XL
• Medikinet XL
• Concerta XL
• Delmosart
• Matoride XL
• Xaggitin XL
• Xenidate XL
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Brand names differ between
countries
Lisdexamfetamine
• UK: Elvanse
• USA & Canada: Vyvanse
• Republic of Ireland: Tyvense
• Brazil: Venvanse
• Chile: Samexid
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Classification of ADHD
medicines
Stimulants
• methylphenidate
• dexamfetamine
• lisdexamfetamine
(Elvanse)
Nonstimulants
• atomoxetine (Strattera)
• guanfacine (Intuniv)
powerful,
act immediately,
alerting,
can only use during day
less powerful,
take time to get going,
slightly sedating,
effect lasts for 24 hours
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NHS doctors are encouraged to
prescribe ‘generically’ using the
generic name on the prescription to
enable a pharmacist to dispense
any medicine with that generic
name, irrespective of brand
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Medicines become available
• If scientific trials show they work
• They are safe and have manageable side-
effects
• They can be made to a high quality
standard
• Their manufacturer is then given a ‘licence’ and
can name their medicine as a brand
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A ‘licence’
• Is a marketing authorisation given to a manufacturer
• Specifies dose, what it’s for, which age groups
• Usually granted on basis of scientific trials in adults
• Most children’s medicines are therefore off-licence
• Nothing to do with doctors but management keen on licensed medicines because ‘safer’
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Local formulary
• List within NHS locally of which drugs
doctors can prescribe
• Hung up on NICE
• Very much driven by cost
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Cost of 30 x 10mg tablets
• ‘methylphenidate’ £3.97 (AAH)
- £5.49 (Kent)
• Tranquilyn £3.97
• Medikinet £5.49
• Ritalin £6.68
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Cost of 30 x 36mg tablets
• Concerta XL £42.45
• Matoride XL £21.22
• Delmosart £21.23
• Xaggitin XL £21.22
• Xenidate XL £21.21
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Either
• ‘methylphenidate’ 10mg x 3 daily for 30
days
£11.91
• Xenidate XL 36mg daily for 30 days
£21.21
• Concerta XL 36mg daily for 30 days
£42.45
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methylphenidate
(lis)dexamfetamine
atomoxetine guanfacine
stimulant non-stimulant
Traditional guidance algorithmabuse risk? tics? duration issue?sleep?patient choice
Decide stim/nonstim on basis of
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methylphenidate
(lis)dexamfetamine
atomoxetine guanfacine
stimulant non-stimulant
NICE 2018 ng87 algorithm
•Relegates non-stimulants to 3rd line only
•Removes consideration of patient/family
preference (Nice TA98)
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BUT
• Atomoxetine is a noradrenaline re-uptake
blocker – just like methylphenidate and
lisdexamfetamine
• Not likely to work when these have been
tried and failed
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Problem 1.
• Medium duration XLs are not the same
• So, for them, doctors are instructed in the
BNF, (the ‘prescribers’ bible’) to use brand
names
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MPH blood levels
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Bazire chart
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Problem 2
‘Bioequivalence’
• term used by licensing authorities (MHRA, EMA, FDA etc)
• a ‘bioequivalent’ new ‘generic’ drug need only produce 80% of the blood levels produced by original brand
• bioequivalence is not exact equivalence– not many doctors and pharmacists know that !
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Generics
• Only need to meet bioavailability of lead brand product by 80-125% www.ema.europa.eu. Check in Statement of Product Characteristics (SPC) on linewww.medicines.org.uk
– Matoride XL, Delmosart, Xaggitin XL pK data in the SPC are identical word for word to ConcertaXL (!)
– Xenidate XL is a different design and releases appreciably less than Concerta XL 110.5 cf. 125.4 ng/ml/h (11% less)
Statement by e.g. EMA that drug is bioequivalent to the original lead product doesn’t mean it’s exactly the same
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methylphenidate
(lis)dexamfetamine
atomoxetine guanfacine
stimulant non-stimulant
NICE 2018 ng87 algorithm
•Relegates non-stimulants to 3rd line only
•Removes consideration of patient/family
preference (Nice TA98)
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How to choose between
atomoxetine (Strattera) and
guanfacine (Intuniv)?• Guanfacine
– may reduce tics
– no appetite suppression
– sleepiness
• Atomoxetine
– may help ADD when slow cognitive processing the problem
– gut problems
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Virtually no UK guidance on
combinations
• Stimulant plus guanfacine (Intuniv)
• Adding different medicines for sleep
problems
• Adding low-dose aripiprazole or
risperidone
• Adding SSRIs for anxiety
etc etc
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Side-effects: a few points
• Stimulants commonly cause appetite
suppression and difficulty getting off to
sleep
• Less commonly stomach pain or
headache
• Non-stimulants have a different profile
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Long-term stimulants
• Can cause slowing of height growth
though this is not common
• Cause growth of frontal lobe cortex
• May (one study) cause nerve tracts in
brain to become more organised
• Are not addictive in the treatment of ADHD
• Do not cause psychosis in treatment
doses
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Now, what else?