Download EA_QA47.7Methylphenidateinadults

Medicines Q&As
Q&A 47.6
Can methylphenidate be used for adults with attention deficit
hyperactivity disorder (ADHD)?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Date prepared: 11th August 2015
Background
ADHD is a behavioural syndrome characterised by the core symptoms of hyperactivity, impulsivity
and inattention. Symptoms of ADHD can overlap with symptoms of other related disorders, in adults
they include personality disorders, bipolar disorder, obsessive compulsive disorder and substance
misuse. (1) ADHD is thought to affect about 3–9% of school-age children and young people in the UK,
and about 2-4% of adults worldwide, including the UK, although higher prevalences have been
reported in The Netherlands (5%) and France (7.3%). (1-4) Adult ADHD is widely under-recognised.
(1, 5) Most young people with a diagnosis of ADHD will go on to have significant difficulties in
adulthood, which may include continuing ADHD, personality disorders, emotional and social
difficulties, substance misuse, unemployment and involvement in crime. (1) At least 25% of children
with ADHD will still have symptoms at the age of 30. (6) Adults may receive a first diagnosis of ADHD
having never been diagnosed as a child but have a history of symptoms, or have late onset ADHD,
which is considered controversial and relatively rare. (2) ADHD has been diagnosed for the first time
in adults aged 55-70 years. (7)
A clinical guideline on the diagnosis and management of ADHD in children, young people and adults
was issued by the National Institute for Health and Clinical Excellence (NICE) in September 2008 and
updated in March 2013. (1) It states that people with ADHD require integrated care that addresses a
wide range of personal, social, educational and occupational needs. Care should be provided by
adequately trained healthcare and education professionals.
Adults presenting with symptoms of ADHD who do not have a childhood diagnosis should be referred
for assessment by a mental health specialist trained in the diagnosis and management of ADHD.
Adults who have previously been treated for ADHD as children or young people and have symptoms
suggestive of continuing ADHD should be referred to adult psychiatric services for assessment. Drug
treatment for adults with ADHD should always form part of a comprehensive treatment programme
that addresses psychological, behavioural and educational or occupational needs. Drug treatment is
first line treatment for adults with ADHD with either moderate or severe levels of psychological, social
and/or educational or occupational impairment. (1)
Answer
The NICE clinical guideline states that following a decision to start drug treatment in adults with
ADHD, methylphenidate should normally be tried first. If methylphenidate is ineffective or
unacceptable, atomoxetine or dexamfetamine can be tried. (1) There are methylphenidate
preparations available in the UK with information on administration to adults in their summary of
product characteristics (SPC). Concerta XL, Matoride XL and Medikinet XL (10-60mg) can be used in
adolescents whose symptoms persist into adulthood and who have shown clear benefit from
treatment, so it may be appropriate to continue treatment into adulthood. However, starting treatment
with these preparations in adults is not appropriate. Safety and efficacy have not been established for
the initiation of treatment in adults or the routine continuation of treatment beyond 18 years of age. If
treatment withdrawal has not been successful when an adolescent has reached 18 years of age
continued treatment into adulthood may be necessary. The need for further treatment of these adults
should be reviewed regularly and undertaken annually. (8-16)
The other methylphenidate preparations currently available in the UK are not licensed for use in
adults (17-20). However, methylphenidate hydrochloride is licensed for use in adults in America. (21)
Atomoxetine is licensed for use in adults with ADHD in the UK. The presence of pre-existing
symptoms in childhood should be confirmed. (22)
From the NHS Evidence website www.evidence.nhs.uk
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Medicines Q&As
The NICE guideline development group (GDG) identified a number of studies published between
1976 and 2007 that assessed the efficacy and safety of pharmacological treatments for ADHD.
However, a large majority were excluded as they lacked validated outcome measures. (23) The use
of methylphenidate in adults is based on the results of 3 studies – see table 1. The NICE GDG
summarised that in adults with ADHD, high dose methylphenidate showed evidence of a reduction in
ADHD symptoms as rated by an investigator but a small effect of improvement in medium doses as
measured from self-reports. There was also evidence of global clinical improvement when compared
with placebo. (23) Only one RCT (24) assessed side effects and indicated that high dose
methylphenidate is more likely than placebo to cause particular side effects: decreased appetite,
gastrointestinal problems, tension, cardiovascular complaints, depression, dizziness, anxiety,
autonomic symptoms, increased energy, tics, skin problems, bruising and sexual problems.
Methylphenidate may reduce the risk of discontinuation when compared with placebo. Long-term
studies of side effects in adults are scarce. Safety reviews have indicated an association between the
use of methylphenidate and sudden death, however, given the lack of background rates the evidence
is inconclusive. The GDG concluded that methylphenidate is effective in reducing ADHD core
symptoms and in producing clinical improvement as rated by investigators in adults with ADHD and
high dose methylphenidate may increase side effects. (23)
Table 1 - Efficacy results from double blind, placebo controlled studies in adults with ADHD
Ref
no.
24
25
26
Study details
Methylphenidate
preparation
36mg SR tablet
[osmotic release
oral system]
Mean daily
dose
80.9  31.8mg
146 adults
R, DB, PC, PD
6 weeks
duration
5mg & 10mg IR
capsules
82 ± 22mg
45 adults
R, DB, PC, CO
6 weeks
duration
10mg IR tablets
149 adults
R, DB, PC
6 weeks
duration
(0.99 ± 0.32
mg/kg)
(1.1 ± 0.24
mg/kg)
Mean total daily
dose not stated
(0.91mg/kg,
range 0.541.04 mg/kg)
Results at study endpoint
66% methylphenidate vs. 39%
placebo subjects reported much
or very much improved on the
CGI Improvement scale and a
>30% reduction in ADHD
symptoms on AISRS (p<0.001).
68% methylphenidate vs. 17%
placebo subjects reported much
or very much improved on the
CGI Improvement scale and a
>30% reduction in ADHD
symptoms on AISRS (p<0.0001).
38% methylphenidate vs. 7%
placebo subjects had a decrease
of at least 2 points on the CGIADHD and a >30% symptom
reduction measured by the DSMIV ADHD rating scale (p=0.003).
Key: R = randomised, DB = double blind, PC = placebo controlled, CO = cross over, PD = parallel
design, SR = sustained release, IR = immediate release, CGI-ADHD = Clinical Global Impression
scale for ADHD (investigator assessment), AISRS = Adult ADHD Investigator System Report Scale,
DSM-IV ADHD = Diagnostic and Statistical Manual of Mental Disorders 4th edition ADHD rating scale
(patient self assessment)
A comparison of the acute efficacy and tolerability of the 2 different methylphenidate preparations
used in the Biederman et al (24) and Spencer et al (25) studies concluded that once daily doses of
SR methylphenidate had similar efficacy to three times daily doses of IR methylphenidate. (27)
The NICE GDG reviewed the guideline and decided in February 2014 that it should be updated,
particularly because atomoxetine is now licensed for starting treatment in adults with ADHD. (28)
A systematic review of 8 meta-analyses assessing pharmacological and psychosocial interventions
for adults with ADHD indicates that stimulants (including methylphenidate) are effective in decreasing
ADHD symptoms on a short-term basis with a medium to large effect size. Short-acting stimulants
might be superior to long-acting stimulants, but no data on difference in adherence are available for
the comparison of these 2 types of formulation. (29)
From the NHS Evidence website www.evidence.nhs.uk
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Medicines Q&As
A Cochrane systematic review (11 trials, n=474) which evaluated the efficacy and tolerability of IR
methylphenidate versus placebo in the treatment of adults with ADHD showed that IR
methylphenidate decreased hyperactivity, impulsivity and inattentiveness compared to placebo.
Subgroup analysis comparing high versus low doses did not indicate that higher doses of IR
methylphenidate were associated with greater efficacy. The trial data suggest that adverse effects
from IR methylphenidate for adults with ADHD are not of serious clinical significance. (30)
Evidence based guidelines for the pharmacological management of ADHD from the British
Association for Psychopharmacology in 2014 recommend use of methylphenidate as a first line
stimulant drug. Response to treatment should be assessed in follow up visits using rating scales to
objectively check symptoms before and after medication. The clinician should increase the dose until
optimal management of symptoms is achieved. If the patient cannot tolerate higher doses or no effect
is seen after a trial of adequate duration, a switch to a non-stimulant drug is recommended. (31)
Since the NICE clinical guideline publication, a number of papers have reviewed and assessed the
efficacy, tolerability and long term use of IR and SR methylphenidate in adults with ADHD. A review of
controlled and naturalistic studies demonstrate efficacy for both methylphenidate formulations and
indicate that use of methylphenidate results in statistically significant improvement of ADHD
symptoms according to various rating scales. (32-34) Quality of life is improved as well. (35) Some
adults with ADHD do not have a sufficient response to methylphenidate, to date no reliable
neurobiological markers of treatment response have been identified. (36) It has been suggested that
ADHD in adults could be split into 2 presenting types- inattentive and emotional dysregulation. Those
with emotional dysregulation have a greater severity of symptoms, although both types respond well
to methylphenidate. (37) Patients with a greater severity of ADHD have a good response to
methylphenidate independent of co-morbidities. (38) A meta-regression analysis of the efficacy of
methylphenidate for adults with ADHD showed an improvement in symptoms in a dose dependent
fashion. (39) The efficacy of methylphenidate appears to be reduced in patients with comorbid
disorders. (33, 39, 40)
The studies included in the NICE clinical guideline were only of 6 weeks duration, other studies have
been conducted from 24 weeks to more than 4 years. (32, 33) A naturalistic follow up study showed
that treatment of ADHD in adults for more than 2 years was associated with better functioning than
treatment for 2 years or less. (33)
All the studies showed quite high rates of discontinuation of methylphenidate, some over 50%. In
many cases, discontinuation was due to adverse effects or lack of efficacy due to the low doses used
in the studies. (32, 33) There is a positive correlation between dropout rate and the dose of
methylphenidate. (34) Post-hoc analysis of a randomised, double blind, placebo controlled trial with
SR methylphenidate 54mg and 72mg suggest that women, newly diagnosed patients, patients with a
substance use disorder and subjects with high educational degrees seem to have a higher risk of
non-adherence and therefore a reduction in improvement in symptoms. (41)
Cardiovascular adverse effects have been noted in the clinical trials, methylphenidate is associated,
on average, with only small elevations in blood pressure and heart rate. Increased risk of sudden
death or ventricular arrhythmia has not been demonstrated in large population based studies. (32)
Summary

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NICE clinical guidelines on the diagnosis and management of ADHD in children, young people
and adults state that following a decision to start drug treatment in adults with ADHD,
methylphenidate should normally be tried first.
Methylphenidate preparations currently available in the UK are not licensed for use in adults.
The SPCs for Concerta XL, Matoride XL and Medikinet XL (10-60mg) say they can be used in
adolescents whose symptoms persist into adulthood and who have shown clear benefit from
treatment, so it may be appropriate to continue treatment into adulthood. However, starting
treatment with Concerta XL, Matoride XL and Medikinet XL in adults is not appropriate.
Methylphenidate is effective in reducing ADHD core symptoms and in producing clinical
improvement in adults with ADHD when assessed against investigator rating scales.
From the NHS Evidence website www.evidence.nhs.uk
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Medicines Q&As
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Improvement in symptoms is dose dependent and sustained release and immediate release
methylphenidate preparations have similar efficacy in adults.
A naturalistic follow up study showed that treatment of ADHD in adults for more than 2 years was
associated with better functioning than treatment for 2 years or less. Co-morbidity at baseline is a
predicter of poorer outcome.
There is a positive correlation between dropout rate and the dose of methylphenidate. Women,
newly diagnosed patients, patients with a substance use disorder and subjects with high
educational degrees seem to have a higher risk of non-adherence.
Methylphenidate is associated, on average, with only small elevations in blood pressure and heart
rate. Increased risk of sudden death or ventricular arrhythmia has not been demonstrated in large
population based studies.
Limitations
This question has only examined the use of methylphenidate for treatment of adults with ADHD. Other
stimulants have also been studied e.g. dexamphetamine, atomoxetine. Non-stimulants that may
provide a response include bupropion, monoamine oxidase inhibitors, lithium and venlafaxine. (2)
References
1. NICE Clinical Guideline 72. Attention deficit hyperactivity disorder: diagnosis and management of
ADHD in children, young people and adults. Issued September 2008, last modified March 2013.
Accessed via http://www.nice.org.uk on 08/07/15.
2. Bazire S. Psychotropic Drug Directory 2014. Lloyd-Reinhold Communications. p34-37
3. McCarthy S, Wilton L et al. The epidemiology of pharmacologically treated attention deficit
hyperactivity disorder (ADHD) in children, adolescents and adults in UK primary care. BMC
Paediatrics 2012; 12: 78 http://www.biomedcentral.com/1471-2431/12/78
4. Brod M, Pohlman B et al. Comparison of the burden of illness for adults with ADHD across seven
countries: a qualitative study. Health and Quality of Life Outcomes 2012; 10: 47
http://www.hqlo.com/content/10/1/47
5. Anon. Adults with ADHD: ignored and under-treated. Drug and Therapeutics Bulletin 2011; 49 (7):
73
6. Taylor D, Paton C, Kapur S. The Maudsley Prescribing Guidelines in Psychiatry, 12 th edition,
2015. Wiley Blackwell. p385-7.
7. Manor I; Rozen S; et al. When does it end? Attention-deficit/hyperactivity disorder in the middle
aged and older populations. Clinical Neuropharmacology 2011; 34 (4): 148-54.
8. Summary of Product Characteristics - Concerta XL 18mg prolonged-release tablets. JanssenCilag Ltd. Accessed via http://emc.medicines.org.uk on 08/07/15 [last revised 16/06/15].
9. Summary of Product Characteristics - Concerta XL 27mg prolonged-release tablets. JanssenCilag Ltd. Accessed via http://emc.medicines.org.uk on 08/07/15 [last revised 16/06/15].
10. Summary of Product Characteristics - Concerta XL 36mg prolonged-release tablets. JanssenCilag Ltd. Accessed via http://emc.medicines.org.uk on 08/07/15 [last revised 16/06/15].
11. Summary of Product Characteristics - Concerta XL 54mg prolonged-release tablets. JanssenCilag Ltd. Accessed via http://emc.medicines.org.uk on 08/07/15 [last revised 16/06/15].
12. Summary of Product Characteristics - Matoride XL 18mg prolonged-release tablets. Sandoz Ltd.
Accessed via http://emc.medicines.org.uk on 08/07/15 [last revised 17/02/15].
13. Summary of Product Characteristics - Matoride XL 36mg prolonged-release tablets. Sandoz Ltd.
Accessed via http://emc.medicines.org.uk on 08/07/15 [last revised 06/02/15].
14. Summary of Product Characteristics - Matoride XL 54mg prolonged-release tablets. Sandoz Ltd.
Accessed via http://emc.medicines.org.uk on 08/07/15 [last revised 06/02/15].
15. Summary of Product Characteristics - Medikinet XL. Flynn Pharma Ltd. Accessed via
http://emc.medicines.org.uk on 08/07/15 [last revised 08/11/13].
16. Summary of Product Characteristics - Medikinet XL 50mg and 60mg Modified Release Capsules
Hard. Flynn Pharma Ltd. Accessed via http://emc.medicines.org.uk on 08/07/15 [last revised
17/06/14].
17. Summary of Product Characteristics - Equasym XL 10mg, 20mg & 30mg capsules. Shire
Pharmaceuticals Ltd. Accessed via http://emc.medicines.org.uk on 08/07/15 [last revised
10/03/14].
18. Summary of Product Characteristics - Ritalin tablets. Novartis Pharmaceuticals UK Ltd. Accessed
via http://emc.medicines.org.uk on 08/07/15 [last revised 05/05/15].
From the NHS Evidence website www.evidence.nhs.uk
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Medicines Q&As
19. Summary of Product Characteristics - Medikinet tablets. Flynn Pharma Ltd. Accessed via
http://emc.medicines.org.uk on 08/07/15 [last revised 21/12/11].
20. Summary of Product Characteristics - Medikinet XL 5mg. Flynn Pharma Ltd. Accessed via
http://emc.medicines.org.uk on 07/08/15 [last revised 21/12/11].
21. DRUGDEX® Drug Evaluation – methylphenidate. DRUGDEX electronic version, Thomson
Micromedex, USA. Accessed via http://www.thomsonhc.com on 07/06/13.
22. Summary of Product Characteristics – Strattera 10mg, 18mg, 25mg, 40mg, 60mg, 80mg or
100mg hard capsules. Eli Lilly and Company Ltd. Accessed via http://emc.medicines.org.uk on
02/07/13 [last revised 28/05/13].
23. National Collaborating Centre for Mental Health. ADHD. Diagnosis and management of ADHD in
children, young people and adults. The British Psychological Society and The Royal College of
Psychiatrists, 2009. Accessed via http://www.nice.org.uk on 14/07/15.
24. Biederman J, Mick E et al. A randomised, placebo-controlled trial of OROS methylphenidate in
adults with attention-deficit/hyperactivity disorder. Biological Psychiatry 2006; 59: 829-35.
25. Spencer T, Biederman J et al. A large, double-blind, randomised clinical trial of methylphenidate
in the treatment of adults with attention-deficit/hyperactivity disorder. Biological Psychiatry 2005;
57: 456-63.
26. Kooij JJS, Burger H et al. Efficacy and safety of methylphenidate in 45 adults with attentiondeficit/hyperactivity disorder. A randomised placebo-controlled double-blind cross-over trial.
Psychological Medicine 2004; 34: 973-82.
27. Biederman J, Mick EO et al. Comparative acute efficacy and tolerability of OROS and immediate
release formulations of methylphenidate in the treatment of adults with attentiondeficit/hyperactivity disorder. BMC Psychiatry 2007; 7: 49.
28. NICE Centre for Clinical Practice – Surveillance Programme. Surveillance review of CG72:
ADHD. Recommendation for Guidance Executive. Feb 2015
http://www.nice.org.uk/guidance/cg72/resources/attention-deficit-hyperactivity-disorder-adhdsurveillance-review-decision3
29. Moriyama TS, Polanczyk GV, Terzi FS et al. Psychopharmacology and psychotherapy for the
treatment of adults with ADHD-a systematic review of available meta-analyses. [Review]. CNS
Spectrums 2013; 18: 296-306.
30. Epstein T, Patsopoulos NA, Weiser M. Immediate-release methylphenidate for attention deficit
hyperactivity disorder (ADHD) in adults. Cochrane Database of Systematic Reviews 2014, Issue
9. Art. No.: CD005041. DOI: 10.1002/14651858.CD005041.pub2.
31. Bolea-Alamanac B, Nutt DJ, Adamou M et al. Evidence-based guidelines for the pharmacological
management of attention deficit hyperactivity disorder: Update on recommendations from the
British Association for Psychopharmacology. Journal of Psychopharmacology 2014; 28: 179-203.
http://www.bap.org.uk/pdfs/ADHD_Guidelines.pdf
32. Fredriksen M, Halmoy A, Faraone SV et al. Long-term efficacy and safety of treatment with
stimulants and atomoxetine in adult ADHD: A review of controlled and naturalistic studies.
European Neuropsychopharmacology 2013; 23: 508-27.
33. Lensing MB, Zeiner P et al. Four year outcome in psychopharmacologically treated adults with
attention-deficit/hyperactivity disorder: a questionnaire survey. Journal of Clinical Psychiatry 2013;
74 (1): e87-93
34. Santosh PJ, Sattar S et al. Efficacy and tolerability of pharmacotherapies for attention-deficit
hyperactivity disorder in adults. CNS Drugs 2011; 25 (9): 737-63
35. Mattos P, Louza MR, Fernandes Palmini AL et al. A multicentre, open-label trial to evaluate the
quality of life in adults with ADHD treated with long-acting methylphenidate (OROS MPH):
Concerta quality of life (CONQoL) study. Journal of Attention Disorders 2013; 17 (5): 444-8.
36. Retz W, Retz-Junginger P. Prediction of methylphenidate treatment outcome in adults with
attention-deficit/hyperactivity disorder (ADHD). Eur Arch Psychiatry Clin Neurosci 2014; 264
(suppl1): S35-43.
37. Reimherr FW, Marchant BK, Gift TE et al. Types of adult attention-deficit hyperactivity disorder
(ADHD): baseline characteristics, initial response, and long-term response to treatment with
methylphenidate. Atten Def Hyp Disord 2015; 7: 115-128.
38. Victor MM, Rovaris DL, Salgado CAI et al. Severity but not comorbidities predicts response to
methylphenidate in adults with attention-deficit/hyperactivity disorder. Results from a naturalistic
study. J Clin Psychopharmacol 2014; 34: 212-7.
From the NHS Evidence website www.evidence.nhs.uk
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Medicines Q&As
39. Castells X, Ramos-Quiroga JA et al. Efficacy of methylphenidate for adults with attention-deficit
hyperactivity disorder. A meta-regression analysis. CNS Drugs 2011; 25 (2): 157-69
40. Fredriksen M, Dahl AA, Martinsen EW et al. Effectiveness of one-year pharmacological treatment
of adult attention-deficit/hyperactivity disorder (ADHD): An open-label prospective study of time in
treatment, dose, side-effects and comorbidity. European Neuropsychopharmacology 2014; 24:
1873-84.
41. Kooji JJS, Rosler M et al. Predictors and impact of non-adherence in adults with attentiondeficit/hyperactivity disorder receiving OROS methylphenidate: results from a randomized,
placebo-controlled trial. BMC Psychiatry 2013;13:36
http://www.biomedcentral.com/1471-244X/13/36
Quality Assurance
Prepared by
Katie Smith, East Anglia Medicines Information Service
Date Prepared
11th August 2015
Checked by
Sarah Cavanagh, East Anglia Medicines Information Service
Date of check
21st August 2015
Search strategy
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Embase: [[ATTENTION DEFICIT DISORDER/ AND ADULT/] AND METHYLPHENIDATE] [Limit
to: Publication Year 2013-2015 and Human and (Human Age Groups Adult 18 to 64 years) and
English Language and (Clinical Trials Clinical Trial)]
Medline: [ATTENTION DEFICIT DISORDER WITH HYPERACTIVITY/ AND ADULT/] AND
METHYLPHENIDATE/ [Limit to: Publication Year 2013-2015 and (Publication Types Clinical Trial,
All) and Humans and (Age Groups All Adult 19 plus years) and English Language]
In-house database/resources: search terms = methylphenidate, hyperkinetic syndrome, adult
Electronic Medicines Compendium: search term = methylphenidate, adults, ADHD
NICE Evidence: search terms = methylphenidate + adult + hyperkinetic syndrome
DrugDex methylphenidate drug evaluation: ADHD, adults
From the NHS Evidence website www.evidence.nhs.uk
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