adhd treatment updates

By the end of this presentation

you should know more about..

• Evidence base

• Drugs used in Adult ADHD and their side effects

• Shared care protocols

• How to monitor treatment and when to refer back to

specialist

Recommend reading

NICE guidelines for treatment of ADHD [CG72] (2008-

updated 2013)

Summary of the guidelines for the pharmacological

management of ADHD recommendations from the British

Association for Psychopharmacology (Bolea-Alamañac at

al, 2014)

European consensus statement on diagnosis and

treatment of adult ADHD: The European Network Adult

ADHD (Kooij et al, 2010)

Two important neurotransmitters:

(dopamine, noradrenaline)

Responsible for most functional impairment in ADHD

There is impairment in neurotransmitters' function and 70% of patients report improvement with medication

The improvement is dramatic

Side effects are transient and not severe (usually)

Neurobiological dysfunction in ADHD

This has been demonstrated by numerous

literature and brain imaging studies

The most effective treatment is to target this

neurotransmitters dysfunction

Unless this is done, other interventions may not

be so effective

Substance Misuse in ADHD

The prevalence is higher in adults with ADHD

The onset is typically earlier, last longer, and

slow to remit (compared to non ADHD adults)

Early treatment reduce risk of drug abuse in

future (results of meta-analysis review by

Wilens et al, 2003 and case control study by

Wilens et al, 2008)

ADHD in older people

ADHD is not “outgrown” in older persons

The prevalence is similar across all ages (3-5%)

There are 15 case studies of older patients (67-81 yrs)

successfully treated with stimulant medication

Close monitoring of physical health (especially

cardiovascular side effects) during treatment

( Michielsen et al, 2012, Das et al, 2014)

Aims of Drug Treatment

To treat the core symptoms:

Inattentive ± hyperactive, impulsive

To treat the associated impairment:

Educational, learning problems, problems due to poor

performance at work (clumsiness, attention problems)

To treat comorbidities:

Mood and anxiety treatment has better outcome if ADHD is

treated. Combined treatment (for ADHD and for the

comorbidity) is the rule rather than the exception

Impact of non-treatment

Higher rates of academic failure

Low occupational status

Increased risk of substance use disorders (tobacco,

alcohol or drugs)

Accidents and delinquency

Fewer social relationships or friends

Controversial Treatments for

ADHD

Dietary modification (avoiding artificial additives,

sugars, etc...)

Dietary supplements: vitamins or anti-oxidants,

algae, omega 3.

No established evidence for the effectives and

safety of these treatments.

Treatment priorities in ADHD

First treat most severe disorder, usually affective

disorders, substance misuse, then treat ADHD

In case of personality disorder: first treat ADHD

Treatment of milder depressive and anxiety

disorders may be delayed and re-assessed after

ADHD treatment (may improve significantly)

Types of non-pharmacological

treatments

Psycho-education very important component of treatment.

Cognitive-behavioral treatment: to improve self-confidence, self esteem

Coaching

Others: Meta-cognitive therapy (MCT), Cognitive remediation programs (CRP) and Mindfulness based therapies

Medications for ADHD

Are safe and effective but need specialist input

The doses for adults can be more difficult to determine, as most studies were done on children

Require gradual titration and monitoring to “fine tune” according to the individual needs and daily life activities

Drug treatments for adults with ADHD should always form part of a comprehensive treatment (NICE)

Prevalence of treatment in the adult

in UK

Less than 10% of adults with ADHD requiring medication

are thought to receive treatment

High discontinuation rate during transition from adolescents

to adulthood (16-18 years) (McCarthy et al., 2009).

In contrast to children ADHD treatment, NICE recommends

that pharmacological interventions are always first line in

adults (NICE, 2008).

Patients’ Concerns Regarding

Medications

My change my personality, dull, become like a “zombie”?

I will become a “junkie”, or people will think I am one

Effect on growth

Induce tics (or make them worse)

Effect on sleep, appetite, sex

I need to use it all my life

Licensed indications

Currently only atomoxetine is licensed for treatment of

adults with ADHD provided that it was started before

the age of 18.

The prescription of atomoxetine for the first time after

the age of 18 and the prescription of stimulants is “off-

label”.

But stimulant medications are supported by NICE,

BAP & European guidance and the BNF.

Summary of NICE GuidelinesMedication is the first-line treatment in adults

Methylphenidate is the first-line drug

If methylphenidate is ineffective or unacceptable then atomoxetine or dexamphetamine can be tried 2nd line

In the following situations:

1. Residual symptoms

2. Poor or no response

3. Medication is not an option

4. The patient refuses medication

........then consider CBT

Controlled Drugs

Methylphenidate and dexamfetamine are schedule 2

controlled drugs (CD) thus are subject to prescription

requirements.

Hence prescriptions must states the form and strength

of preparation (e.g. 10mg tablets); the dose (e.g. 10mg

TDS) and total quantity or number of dose units in

words AND figures (e.g. 500 mg = Five Hundred

milligrams).

A prescription can be given for a maximum of 28 days.

Classes of Medication

Stimulants

Methylphenidate

Amphetamine compounds

Dextroamphetamine

Lisdexamfetamine

Non-stimulant

Atomoxetine

Antidepressants

Tricyclics

Bupropion

Antihypertensives

Clonidine

Guanfacine

Miscellaneous

Combined pharmacotherapy

Modafinil

Venlafaxine

Neuroleptics (only in severe cases with monitoring)

Stimulants

Have been used for decades (treatment of ADHD since 1960s)

Available in prolonged release formulations (recommended)

Use is supported by more than 250 randomised controlled studies over 40 years

They enhance dopamine levels by blocking pre-synaptic dopamine transporter

Almost immediate effects is noticed with short acting formulation (within 20 minutes)

(Faraone et al 2003, Volkow et al 2002, Pietrzak at el 2006)

Advantages of Extended-Release

Formulations of Stimulants

They provide prolonged and sustained level of medication spread throughout the day

The onset of the action and end is smoother, which reduces the symptoms fluctuations during the day

May fit better around school, work commitments

Better compliance, less doses

May reduce diversion and abuse

Substance misuse and medication

Not widely reported in the UK.

To provide a sensation of “high”, the stimulant (short acting)

should be injected or snorted.

The risks of abuse can therefore be largely avoided by use

of long-acting formulations of stimulants.

The prodrug lisdexamfetamine is the first pro-drug licensed

in Europe for ADHD and has a very low abuse potential and

is a good alternative to immediate-release dexamfetamine.

Management of some of the

common side effects

Appetite loss

Monitor weight before and after treatment

regularly

Take the medication with or after meals

Eat regularly

Use medication holidays

Insomnia

Explore pre-treatment sleep pattern (ADHD is commonly associated with delayed sleep onset and insomnia)

Advice about sleep hygiene

Reduce the dose, or switch to shorter acting stimulant

Consider adjunctive medication (e.g., melatonin, clonidine)

Irritability

Assess onset (when the drug level peaks: too high dose, or when the drugs wears off: rebound symptoms)

Review the dose

Assess for comorbidity (is irritability part of anxiety/mood symptoms)

Consider combined treatment

Methylphenidate

Methylphenidate hydrochloride (5, 10, 20) including

Medikinet®

Duration of action: 3-4 hours

Dose: 5 mg 2–3 times daily increased if necessary at weekly

intervals according to response, max. 100 mg daily in 2–3

divided doses

Evening dose If effect wears off in evening (with rebound

hyperactivity) a dose at bedtime may be appropriate

(establish need with trial bedtime dose)

Concerta® XL tablet (Janssen)

Schedule 2 controlled drug

22% immediate-release component, 78% modified-release

Dose: 18 mg, 27 mg, 36 mg.

Initially 18 mg once daily in the morning, adjusted at weekly

intervals according to response, max. 108 mg daily

15 mg of standard-release methylphenidate is equivalent to 18

mg Concerta® XL 18 mg once daily

Equasym XL® capsules (Shire)


10 mg 20 mg 30 mg


Dose: initially 10 mg once daily in the morning before

breakfast, increased gradually at weekly intervals if

necessary, max. 100 mg daily

Contents of capsule can be sprinkled on a tablespoon of

apple sauce (then swallowed immediately without chewing)

Medikinet XL® capsules (Flynn)


5 mg 10 mg 20 mg 30 mg 40 mg


Dose: initially 10 mg once daily in the morning with breakfast,

adjusted at weekly intervals according to response, max. 100 mg

daily

Contents of capsule can be sprinkled on a tablespoon of apple

sauce or yoghurt (then swallowed immediately without chewing)

Stimulants Effects

Improved sustained attention

Reduced distractibility

Reduced impulsivity

Improve work performance and academic work

Positive effect on behaviour (reduces aggression and

disruptive behaviour)

Effective in 75% of adult ADHD cases.

Stimulants Side Effects

Insomnia

Decreased Appetite (in 50-60%): Weight Loss

Headaches

Stomach aches (20-40%)

Mood changes/dysphoria

(Mild) Increases in Heart Rate and Blood Pressure

Tics (very rarely Tourette syndrome)

Psychosis

Seizures

Tolerance and dependence?

Non-Stimulant medication (second

line treatment option)

Noradrenaline reuptake inhibitor

-Strattera (atomoxetine)

Antidepressants (various mechanism of action)

buproprion

nortriptyline

desipramine

Alpha-2 Agonists

clonidine

guanfacine

Atomoxetine (Strattera)

Potent pre-synaptic, noradrenergic transport blocker

with low affinity for other neurotransmitters

Structurally similar to Fluoxetine

Optimal effects seen at 2 weeks

May be given as single daily dose or bd

Dispensed in a capsule that cannot be opened

Indications

Severe side effects to stimulants

If comorbidity: tics; substance abuse

Atomoxetine Dose

Initial: 40 mg once daily increased after at least 1 week to 80 mg

Usual maintenance dose is 80-100 mg daily

Adverse effects: hepatotoxicity, suicidal events, cardiovascular (increased p, bp), growth

Not scheduled

Only medication approved for adult ADHD

Atomoxetine Side Effects

Appetite decreased, dry mouth, nausea (>10%) Usually

settles after 1st month of therapy

Insomnia >10%

Abdominal pain, constipation, dyspepsia,

Weight decrease 1-10% Usually settles after initial weight

loss

Palpitations, tachycardia, 1-10%

Erectile dysfunction, irregular menstruation,

Blood pressure increased 0.1-1% Monitor. Discontinue if

clinically indicated

Liver toxicity 0.001-0.1% Discontinue drug. Refer back to

consultant

Post-marketing Reports

Suicide-related events

Aggression, hostility and emotional labiality

Psychosis (including hallucinations)

Seizure

QT interval prolongation

Abnormal liver function tests, jaundice, hepatitis

Cautions

Methylphenidate: history of seizures, tics or family

history of Tourette or other movement disorders, known

drug dependence/history of drug

dependence/alcoholism, depression, psychosis.

Atomoxetine: Cardiovascular disease, QT interval

prolongation, psychosis/mania, history of seizures,

aggressive behaviour/hostility/emotional labiality,

hepatic impairment, pregnancy and lactation.

Contra-indication

Methylphenidate: anorexia nervosa, severe hypertension,

hyperthyroidism, angina pectoris, cardiac arrhythmia

Atomoxetine: Concomitant use or use within 2 weeks of

MAOI, narrow-angle glaucoma.

Interactions

Alcohol: Effects of methylphenidate possibly enhanced by

alcohol.

Methylphenidate possibly inhibits metabolism of SSRI’s and

TCA’s.

Metabolism of atomoxetine possibly inhibited by fluoxetine

and paroxetine

Antipsychotics: methylphenidate possibly increases side

effects of risperidone. Increased risk of ventricular

arrhythmias when atomoxetine given with antipsychotics

that prolong QT interval.

Shared Care Protocols

Funding threatens these protocols

The specialist will initiate treatment

Transfer of prescribing responsibility to GP when the patient’s condition is stable and dose is specified

The GP should agree on this transfer

The specialist will continue to supply prescriptions until transfer of the responsibilities.

There should be regular review of the patient (by the specialist)

The specialist give advice on when and how to change the dose, discontinue or refer back

The GP will monitor patient’s pulse, BP and weight

Pre-treatment assessment

Full history with a basic physical exam including height, weight, pulse, blood pressure, and heart and lung auscultation

If there is family or personal history of heart disease or the cardiovascular examination is abnormal an ECG is recommended.

Risk of self-harm and substance misuse should also be assessed.

In the case of atomoxetine, previous history of liver disease should be evaluated.

Clinical monitoring

To be done by the GP (if in agreement with the specialist) in

accordance with NICE recommendations

Weight: To be measured 3 and 6 months after initiation and

six monthly thereafter.

If evidence of weight loss monitor BMI, if weight loss

persists refer back to consultant.

Heart rate and Blood pressure: Chart before and after each

dose change and routinely every three months. Sustained

resting tachycardia, arrhythmia or clinically significant high

systolic blood pressure (on two occasions: consider dose

reduction and refer to specialist)

Duration of treatment

Should be continued “as long as clinically effective” with

regular reviews at least annually.

Effects of dosage changes or no treatment periods should

be evaluated.

Drug holidays may be useful to ascertain the need of

continuation of treatment.

ADHD in Pregnancy

Amphetamine, lisdexamfetamine,

methylphenidate, atomoxetine, bupropion, and

modafinil are all category C by FDA classification

(Bazire, 2012).

This category includes drugs where animal

studies have reported some harm without there

being any robust evidence in humans.

Both continuing and stopping drug treatment

carries risk.

Medication in Breastfeeding

Very little knowledge

Drugs licensed for children in general less risky

than those that have not been used in this

population.

A recent systematic review supports the idea that

very little methylphenidate reaches the infant

during breastfeeding (Bolea-Alamanac et al., 2013)

Conclusion

Treatment of adult ADHD is crucial and it is the responsibility of

primary and secondary care.

Treatment associated with significant benefits to the person and

society.

There are clear guidance on efficacy of treatment with stimulants

and non-stimulants

Addressing co-morbidity is important.

Developing local shared protocols throughout the UK is crucial

References

NICE, BAP and European consensus

Wilens TE, Faraone SV, Biederman J, Gunawardene S. Does stimulant therapy of attention-

deficit/hyperactivity disorder beget later substance abuse? A meta-analytic review of the literature.

Pediatrics. 2003 Jan;111(1):179-85.

Wilens TE, Adamson J, Monuteaux M, Faraone SV, et al. Impact of Prior Stimulant Treatment for

Attention-Deficit Hyperactivity Disorder in the Subsequent Risk for Cigarette Smoking, Alcohol, and

Drug Use Disorders in Adolescent Girls. Arch Pediatr Adolesc Med. 2008 October ; 162(10): 916–

921.

Faraone SV, Sergeant J, Gillberg C, Biederman J. The worldwide prevalence of ADHD: is it an

American condition? World Psychiatry. 2003 Jun;2(2):104-13.

Volkow ND, Wang GJ, Fowler JS, Logan J, et al. Relationship between blockade of dopamine

transporters by oral methylphenidate and the increases in extracellular dopamine: therapeutic

implications. Synapse. 2002;43:181–187.

Pietrzaka RH, Mollicab CM, Maruffc P, Snyde PJ. Cognitive effects of immediate-release

methylphenidate in children with attention-deficit/hyperactivity disorder

adhd treatment updates

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