what do parents need to know about adhd medicines?
TRANSCRIPT
What do parents need to know
about ADHD medicines?
Professor Peter Hill
What you see
emotional dysregulation
hyperactivity
personal disorganisation
inattention
Is the result of problems in the
brain
Frontal lobe in blue
Some actions of the frontal lobe
• Impulse control
• Social judgement
• Executive functions: planning, self-
awareness
• Holding things in mind ‘working memory’
Cortex is the dark purple outside
layer, full of nerve cells
Brain problem 1
• Immature development and lower activity
of the frontal cortex
Cortex development by age: check the
extent of dark colouration
Shaw 2007Replication Almeida 2010
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
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
Less brain activity on fMRI in
ADHD
Rubia
Normal SPECT brain scan from below
Underside view
SPECT: view from below
ADHD at rest ADHD concentrating
Effect of stimulant medication
ADHD resting ADHD after stimulant
www.amenclinics.comOctober 14, 2019
Brain problem 2
• Inefficient switching from ‘default mode’ to
‘task mode’
Default mode network (purple/pink) vs Task
mode network (red/orange) in normal brain
Kelly 2008 Neuroimage 39:527-537
In ADHD
• inefficient switching between default
(mind-wandering) mode and task mode
Methylphenidate promotes task-
mode network: blue is active
ADHD
ADHD given methylphenidate
Normals
Liddle 2011 JCPP 52:761-771
The point of ADHD medication
• To promote frontal lobe functioning
• In order to compensate for delayed
development and underactivity
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
By increasing neurotransmitters at
the synapse between nerve cells
The synapse
Neurotransmitter 1: Dopamine and
noradrenaline
Methylphenidate blocks the
dopamine transporter so that more
is available
Methylphenidate and Dexamfetamine block
noradrenaline transporter and Dex displaces
noradrenaline and dopamine from vesicles
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
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
The vocabulary of prescribing: the
names of medicines
Chemical2-piperidineacetic acid, α-phenyl-, methyl ester
Scientific generic
methylphenidate
(mee thyle fenni date)
Medicine name: brand
Thus
• Chemical name
• Scientific generic name
• Brand name
Brand names of methylphenidate in the
UK
• Medikinet
• Ritalin
• Tranquilyn
• Equasym XL
• Medikinet XL
• Concerta XL
• Delmosart
• Matoride XL
• Xaggitin XL
• Xenidate XL
Brand names differ between
countries
Lisdexamfetamine
• UK: Elvanse
• USA & Canada: Vyvanse
• Republic of Ireland: Tyvense
• Brazil: Venvanse
• Chile: Samexid
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
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
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
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’
Local formulary
• List within NHS locally of which drugs
doctors can prescribe
• Hung up on NICE
• Very much driven by cost
Cost of 30 x 10mg tablets
• ‘methylphenidate’ £3.97 (AAH)
- £5.49 (Kent)
• Tranquilyn £3.97
• Medikinet £5.49
• Ritalin £6.68
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
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
methylphenidate
(lis)dexamfetamine
atomoxetine guanfacine
stimulant non-stimulant
Traditional guidance algorithmabuse risk? tics? duration issue?sleep?patient choice
Decide stim/nonstim on basis of
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)
BUT
• Atomoxetine is a noradrenaline re-uptake
blocker – just like methylphenidate and
lisdexamfetamine
• Not likely to work when these have been
tried and failed
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
MPH blood levels
Bazire chart
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 !
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
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)
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
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
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
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
Now, what else?