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?