7 ICD-10 versus DSM IV Inattentiveness Impulsivity inattentive Type 314.00InattentivenessImpulsivityDisturbed activity(Hyperactivity)hyperkineticSyndromeF90combinedType314.01hyperactiveimpulsive Type314.01
8 Social/financial status SchoolDelinquencyADHDOccupational statusSocial/financial statusDrug abusePeer relationshipsTraffic accidentsMarital status
9 Statistics 2 - 6 % of pupils (age 6 – 16) show symptoms of AD/HD Hyperactivity is more common in boysin 70 % of the patients, symtomatology calms in adolescence30 % keep symptoms which need therapy in adulthood
13 EtiologyAttention, evaluation of situations, learning and activity are functions which are located in dopaminergic areas of the brainIn animal experiments a depression of dopaminergic function leds to hyperactivity, aggression and worsening of learning procedures
21 DiagnosisHistory and anamnesis including interviews with patient, parents, teachersSymptomatology (differing criterias between DSM IV (AAP) and ICD-10)Rating Scales (CRS, CBCL etc.)Exclusion of other medical disorders (e.g. epilepsy, brain damage, schizophrenia, hyperthyreosis)physical examination including EEG, lab, intelligence testing
23 Treatment of AD/HD always has to combine educational, psychotherapeutical and psychopharmacological methods
24 StimulantsThe use of stimulants started in the 1930‘s when their stimulative effects on the dopamingergic system and their psychotropic effects were discoveredFirst Amphetamine and Metamphetamine were usedFirst descriptions of an use of Methylphenidate in „MCD“ in the 1960‘sDetailed descriptions in the 1980‘s by Wender et al.
27 Mode of actionFirst a paradox way of action was assumed when Methylphenidate, a stimulant, improved attention and hyperactivity of the childrenAD/HD was explained as a dopamine deficit syndrome, which is treated by stimulants by an increase in neurotransmitter releaseThis theory was not able to explain the missing tolerance effect of the drug and its efficacy in non hyperactive „only“ inattentive patients
28 Mode of action Krause et al. Diese SPECT (Single Photon Emission Computed Tomography) Abbildung zeigt die Dichte des Dopamintransporters im sog. Striatum (Gehirnregion) an.Ganz rechts ein gesunder Proband. Ganz links ein unbehandelter Patient mit ADHD, in der Mitte ein Patient mit ADHD nach Methylphenidat-Therapie. Man sieht eine deutliche Reduktion der erhöhten Transporterdichte unter Ritalin®Krause et al.
29 Because of time one example of efficacy only AD/HDBecause of time one example of efficacy only
33 Facts and Problems Onset of action after 20 – 40 minutes Duration of action 2-4 hoursRepeated dosing – often over school-time - mandatoryAcute tolerance requires peaked doses with raising plasma levels over the day and drug free interval at nightStable plasma levels show poor clinical efficacy, sharp increase in plasma levels in the morning required
34 Ritalin® LA - Objectives Fast onset of action in the morning, with a high morning doseDouble peak pharmacokinetic with raising plasma levels over the dayDuration of action about 8 – 10 h to cover schoolday, but not to interfer with sleep at nightEasy to swallow, no food interactionEasy switch from standard medicationIndividualized dosing
36 Ritalin® LA Ritalin® LA 20 mg (n=19) Bimodal Release of Ritalin® LA Achieved Greater ExposureRitalin® LA 20 mg provided a more rapid rise (Tmax) and achieved greater plasma concentrations (Cmax) over the first 8 hours compared with Concerta® 18 mgMarkowitz J, et al. Clin Pharmacokinet. In press.
37 Concerta® - OROS™Concerta® is a trademark of Janssen Cilag, / J&J
38 Ritalin® LA vs. Concerta® Time (h)Concerta® 18 mg (n=19)MPH concentration (ng/mL)Ritalin® LA 20 mg (n=19)Bimodal Release of Ritalin® LA Achieved Greater ExposureRitalin® LA 20 mg provided a more rapid rise (Tmax) and achieved greater plasma concentrations (Cmax) over the first 8 hours compared with Concerta® 18 mgMarkowitz J, et al. Clin Pharmacokinet (2003) 42(4) 1-9
39 Important differences Concerta®Dose strenghts 18, (27), 36, (54) mgInitial dose 22 %Sustained dose 78 %Duration of action up to 12 hCapsule must not be openedRitalin® LADose strenghts 20, 30, 40 mgInitial dose 50 %Sustained dose 50 %Duration of action up to8 hCapsule may be opened and sprinkled on soft foodConcerta® is a trademark of Janssen Cilag, / J&J
40 How to switch ? Switching can be done from day to day Previous methylphenidate doseRecommended Ritalin Uno dose10 mg methylphenidate b.i.dor 20 mg methylphenidate SR20 mg qd15 mg methylphenidate b.i.d30 mg qd20 mg methylphenidate b.i.dor 40 mg of methylphenidate SR40 mg qdSwitching can be done from day to daySwitching sometimes needs new dose adjustmentAlways remind initial 50 % of dose (10 mg, 15 mg, 20 mg)Starting with too high doses may lead to initial side effects and bad compliance !
41 Or what does this mean in daily practice ? PharmacodynamicsOr what does this mean in daily practice ?
42 School Day Efficacy of Ritalin® LA vs. Concerta® Randomized, rater blind, placebo controlled clinical trial36 children, 6-12 years, 29 boys, 7 girlsAll stabilized on 20 mg MPH/die ahead of trial4 way crossover designStudy medication on days 7, 14, 21, 28, standard medication in-betweenSwanson, Kotkin, Alger M-Flynn, Pelham (SKAMP) Attention/Deportment ScaleAge/intelligence-appropriate, 400-question, 10-minute written math test
43 Ritalin® LA vs. Concerta® SKAMP Attention over first 4 hours Change from Baseline (Predose) 0-4 Hours N=36WorseningImprovementRitalin® LA 20 mg-2.481*†Concerta® 18 mg-1.362Concerta® 36 mg-1.55‡1.24Placebo*P=0.015 for Ritalin® LA 20 mg vs Concerta® 18 mg.†P=0.043 for Ritalin® LA 20 mg vs Concerta® 36 mg.‡P<0.001 vs all active treatment groups.
44 Ritalin® LA vs. Concerta® SKAMP Attention over schoolday Change from Baseline (Predose) 0-8 Hours N=36WorseningImprovementRitalin® LA 20 mg-4.481*†Concerta® 18 mg-2.719Concerta® 36 mg-3.244‡3.786Placebo*P=0.074 for Ritalin® LA 20 mg vs Concerta® 18 mg.†P=0.208 for Ritalin® LA 20 mg vs Concerta® 36 mg.‡P<0.001 vs all active treatment groups.
45 Ritalin® LA vs. Concerta® SKAMP Combined Ritalin® LA 20 mgConcerta® 36 mgN=36Concerta® 18 mgPlacebo*†*†*†*Mean change from predose in SKAMP-combined0.51.02.03.04.06.08.0Time (h)*P<0.05 for Ritalin® LA 20 mg vs Concerta® 36 mg.†P<0.05 for Ritalin® LA 20 mg vs Concerta® 18 mg.
46 Strattera® (Atomoxetine, Eli Lilly) Atomoxetine is a norepinephrine-reuptake inhibitor, orginally developed as antidepressant (Pharmacia)Atomoxetine has no dopaminergic activityAtomoxetine is the first non-stimulant approved for treatment of AD/HDAtomoxetine is the first pharmacologic treatment, approved for the use of adult AD/HDOnset of action as with other antidepressants is delayed (4 – 6 weeks at minimum)
47 Strattera® (Atomoxetine, Eli Lilly) Efficacy of Atomoxetine seems to be lower than that of stimulantsCommon side effects are nervousness, sleeplesness, loss of appetite, decreased body weight, sexual dysfunction, especially in boysIn US Atomoxetine gained 15 % market share in AD/HD market within 6 months after launchApproval and launch in EU has been delayed several times – expected currently for H2/2004