Intelligent Prescribing. Optimizing Medication Treatments in ADHD Dr Dave Coghill

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1 Intelligent Prescribing Optimizing Medication Treatments in ADHD Dr Dave Coghill

2 Source Consultant Advisory Board Stock Equity >$10,000 Speaker Research Lilly X X X Janssen/ McNeil X X X UCB X X Shire X X X Medikinet / Flynn X X NHS: HTA MHRN X X

3 Treatment Decisions Severe, pervasive, disabling? Problems at home? Problems at school? Persistent after treatment? Comorbid problems? Home CBT Liaison + self-instruction Medication Taylor, Santosh & Swanson (2002) submitted

4 Treatment Decisions Severe, pervasive, disabling? Problems at home? Problems at school? Persistent after treatment? Comorbid problems? Home CBT Liaison + self-instruction Medication Taylor, Santosh & Swanson (2002) submitted

5 Treatment Decisions Severe, pervasive, disabling? Problems at home? Problems at school? Persistent after treatment? Comorbid problems? Home CBT Liaison + self-instruction Medication Taylor, Santosh & Swanson (2002) submitted

6 Treatment Decisions Severe, pervasive, disabling? Problems at home? Problems at school? Persistent after treatment? Comorbid problems? Home CBT Liaison + self-instruction Medication Taylor, Santosh & Swanson (2002) submitted

7 Treatment Decisions Severe, pervasive, disabling? Problems at home? Problems at school? Persistent after treatment? Comorbid problems? Home CBT Liaison + self-instruction Medication Taylor, Santosh & Swanson (2002) submitted

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9 ADHD Response to Stimulants Meta-analysis of within-subject comparative trials evaluating response to stimulant medications Best Response (Percent) About 70% of patients respond to methylphenidate, 38% 36% 70% respond to amfetamine and overall 26% 95% respond to one or the other 10 0 Dextroamphetamine Methylphenidate Equal response to either Greenhill et al. JAACAP 1996;35:1304. stimulant

10 Response Analysis: LYBI ( 40% Reduction in ADHD RS Total Score) Responders to ATX Nonresponders to ATX Total Responders to OROS Nonresponders to OROS About 40% of patients who do not respond to stimulants, do respond to atomoxetine Total p<.001, Fisher s exact test Patients with at least one week on ATX

11 NICE 2006 The decision regarding which drug to use should be based on the following: the presence of comorbid conditions (for example, tic disorders, Tourette s syndrome, epilepsy) the different adverse effects of the drugs specific issues regarding compliance for example problems created by the need to administer a mid day treatment dose at school the potential for drug diversion and/or misuse the preferences of the child/adolescent and/or his or her parent or guardian.

12 NICE 2008 Methylphenidate should be the first line drug used in pharmacological treatment of ADHD as this has the largest evidence base. Atomoxetine is useful as a second line drug for those who do not respond to, or have problems with, methylphenidate, and as a first line agent in some instances. Antipsychotics are not recommended in the treatment of ADHD. Attention deficit hyperactivity disorder: Diagnosis and management of ADHD in children, young people and adults - NICE guideline Draft for consultation, January 2008

13 NICE 2008 When prescribing methylphenidate for the treatment of children or young people, modified release (MR) preparations should be considered for; Convenience Improving adherence Reducing stigma (because the child does not need to take medication at school) Reducing the problems schools have in storing and dispensing a controlled drug Because of its smoother pharmacokinetic profile. Attention deficit hyperactivity disorder: Diagnosis and management of ADHD in children, young people and adults - NICE guideline Draft for consultation, January 2008

14 NICE 2008 Atomoxetine is generally used as a secondline treatment, but may be considered as a first line treatment in the following circumstances: Comorbid tics or Tourette s disorder Comorbid anxiety disorder Comorbid stimulant substance misuse. Attention deficit hyperactivity disorder: Diagnosis and management of ADHD in children, young people and adults - NICE guideline Draft for consultation, January 2008

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16 Initiating Treatment Psychoeducation Focussing on desired outcome and target symptoms Importance of using standardised ratings and recording baseline information Methylphenidate titration strategies Forced dose Single dose trials Starting with long acting preparations Atomoxetine titration strategies

17 Psychoeducation About the disorder and treatment options About the specific pharmacological interventions and important issues associated with their use What is and is not known Time to response paracetamol model Beliefs about medication Fears about addiction

18 The process of pharmacotherapy Assessment, diagnosis, target symptoms Choose medication Algorithm approach Baseline measurements Determine starting dose, initial target dose and how to get there Look at the literature Take advice Start low go slow but not to slow When reach initial target dose wait expected length of time for therapeutic response to occur Remember that different effects take different times Adverse events often arise earlier than therapeutic effects

19 Target Symptoms and Problems Core ADHD symptoms Behaviour in the home Classroom behaviour Academic functioning Peer group relationships Associated symptoms rage, oppositionality etc.

20 Forced Dose Titration Dundee Maximum Benefit Minimum Dose 4 week titration with weekly dose increments Baseline and weekly monitoring conducted by nurses Standardised forms and assessments 10 item Connors P & Connors T ADHD RS clinician scored CGI S & CGI I clinician scored Side effects may be better rated as other symptoms End of titration Dr and nurse joint visit

21 Not present Other symptoms Present but not impairing Present and impairing Present and severely impairing Insomnia or trouble sleeping Nightmares Drowsiness Nausea Anorexia (Less hungry than other children) Stomach-aches Headaches Dizziness Sad/unhappy Prone to crying Irritable Thoughts of self-harm Suicidal ideation Euphoric/unusually happy Anxious Tics or nervous movements Spaced-out / Zombie-like Less talkative than other children Less sociable than other children Write note

22 Forced Titration Baseline 5mg tds 10mg tds 15mg tds 20mg tds 2 0 ADHD RS Hyp/Imp ADHD RS Inatt CTRS CGAS Low Mood Irritability

23 Single dose trials of MPH 5mg on weekend/holiday morning. Parents introduce cognitively demanding task 1 hour later, observe general effect 10 mg on another weekend/holiday morning (15mg on another in teenagers) Parents draw conclusion as to tolerance and likely effect. If favourable can discuss with prescriber, extend to mornings only during school week with e.g. CTRS R, comparing a.m. vs p.m.

24 Two models for introducing atomoxetine 1. Traditional 0.5 mg/kg/day for 7 days, then 1.2 mg/kg/day 2. German 7 14 days each of 10 mg, 18, mg, 25 mg and so on following capsule size aiming for 1.2 mg/kg/day In both instances hang on at 1.2 mg/kg/day for at least 8 (preferably 12) weeks before either giving up or increasing dose

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26 Monitoring ongoing treatment Teamwork Coherent and consistent protocols Routine measurement Identification of other problems Remember the importance of concordance and adherence

27 Team Treatment Multimodal treatments are often the most appropriate, and one person generally can not do it all The team must be mutually supportive Don t underestimate the role/task of the pharmacotherapist

28 Measurement Clinical improvement Diagnostic specific symptoms Associated symptoms Global measures Combine observer rated and patient rated measures but don t assume they measure the same things USE APPROPRIATE VALID INSTRUMENTS AT APPROPRIATE TIMES

29 Continuing Care Dundee Protocol Regular follow up appointments by doctor and nurse, particularly at the outset of treatment and for those with complex comorbidity Main aims are to monitor medication Identify other problems which require further assessment / treatment The continued routine use of standardised Data capture proforma Assessment tools ADHD RS CGI S & CGI I Side effects Teacher Conners before each appointment Record weight, height and BP at least six monthly

30 OPTIMISING TREATMENT WITH LONG ACTING STIMULANT PREPARATIONS

31 If...you are going to start an extendedrelease stimulant preparation how If... do you decide which one to use? ANSWER The one that best suits that child at that time This will depend on pharmacodynamic profile This is determined by: Methylphenidate or Amfetamine Proportions IR/ER Duration of action Delivery mechanism

32 Methylphenidate Concerta XL, Equasym XL / Metadate CD, Medikinet Retard Duration of action Equasym XL, Medikinet Retard = 8 hours Concerta XL = 12 hours IR / ER proportions Concerta XL = 22 / 78 % Equasym XL = 30 / 70 % Medikinet Retard = 50 / 50 % Banaschewski T et al., Eur Child Adolesc Psychiatry 2006;15(8):

33 Pharmacokinetic Profiles Banaschewski T et al. Eur Child Adol Psych 2006

34 Bioavailability of different MPH-ER Products Mean d,l methylphenidate plasma levels (ng/ml) Ritalin 20 mg BID = 20 mg IR Concerta 54 mg = 12 mg IR Equasym XL 60 mg = 18 mg IR Ritalin LA 40 mg = 20mg IR Time (h) Gonzalez MA, et al. Int J Clin Pharmacol Ther. 2002;40:

35 Medication 0 4 hours -IR 4 8 hours 8 12 hours Equasym XL 10mgs 3mgs 7mgs +/- MPH IR Concerta XL 18 mgs 4mgs 14mgs Methylphenidate IR 5mgs BD/TDS 5mgs 5mgs 5mgs Ritalin LA 10mgs 5mgs 5mgs +/- MPH IR Concerta XL 27 mgs 6mgs 21mgs Equasym XL 20mgs 6mgs 14mgs +/- MPH IR Concerta XL 36mgs 8mgs 28mgs Equasym XL 30mgs 9mgs 21mgs +/- MPH IR Methylphenidate IR 10mgs BD/TDS 10mgs 10mgs 10mgs Ritalin LA 20mgs 10mgs 10mgs +/- MPH IR Concerta XL 45 mgs 10mgs 35 mgs Equasym XL 40 mgs 12mgs 28mgs +/- MPH IR Concerta XL 54mgs 12mgs 42mgs Concerta XL 63 mgs 14mgs 49mgs Methylphenidate IR 15mgs BD/TDS 15mgs 15mgs 15mgs Ritalin LA 30mgs 15mgs 15mgs +/- MPH IR Equasym XL 50mgs 15mgs 35mgs +/- MPH IR Concerta XL 72mgs 16mgs 56mgs Equasym XL 60mgs 18mgs 42mgs Methylphenidate IR 20mgs BD/TDS 20mgs 20mgs 20mgs Ritalin LA 40mgs 20mgs 20mgs +/- MPH IR

36 Medication 0 4 hours (IR) 4 8 hours 8 12 hours Equasym XL 10mgs 3mgs 7mgs +/- MPH IR Concerta XL 18 mgs 4mgs 14mgs Methylphenidate IR 5mgs BD/TDS 5mgs 5mgs 5mgs Ritalin LA 10mgs 5mgs 5mgs +/- MPH IR Concerta XL 27 mgs 6mgs 21mgs

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42 Lunchtime Even after a settled morning seems to be getting into constant bother in playground and at dinner. School observation suggests this is due to breakthrough symptoms rather than any psychosocial probs. Peers avoiding contact, often kept in at breaktime Problems at weekend as haing difficulties at football Switch from IR MPH to either Concerta to see if helps to manage breakthrough symptoms

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45 Changing Treatments Ensuring optimization of current treatment Switching treatment Combining different formulations Combining different medications

46 Questions you could ask before changing to a different drug Have I titrated properly? Is this drug/preparation working well at any times during the day? Have I got good enough information from school Are parents and school in agreement about the effects of the drug? Am I targeting the right symptoms? Is there a behavioural explanation for the drug wearing off What else is going on in patients life / family life? Is the medication working but effects limited by side effects? Have I missed any comorbidity? Is the diagnosis right?

47 European Guidelines Summary of results IR stimulants ER stimulants Atomoxetine Efficacy Effect sizes Numbers needed to treat Efficacy duration Compliance + ++ (?) ++ (?) Dosing flexibility Abuse potential ++ D-AMP: (?) - Costs

48 European Guidelines Summary of recommendations If a child responded to immediate release methylphenidate there could be reasons to move them to extended release If a child had an adverse event on methylphenidate then next step often to move to atomoxetine If a child has failed to respond to methylphenidate, the next option may be dexamfetamine or atomoxetine Choice of extended release preparation will depend on profile of action over time