Stimulant Treatment of ADHD

Transcription

1 Stimulant Treatment of ADHD Thomas J. Spencer, MD Massachusetts General Hospital Harvard Medical School

2 Disclosures Shire Laboratories Department of Defense FDA Alcobra Lundbeck Inc. Consultant Research Support Research Support Consultant, Advisory Board, research support Consultant, Research Support Shire Laboratories Inc. Sunovion Consultant Consultant, Research Support Dr. Spencer receives research support from Royalties and Licensing fees on copyrighted ADHD scales through MGH Corporate Sponsored Research and Licensing. Dr. Spencer has a US Patent Application pending (Provisional Number 61/ ), through MGH corporate licensing, on a method to prevent stimulant abuse. 2

3 3 nida.gov

4 % Baseline Effects of Methylphenidate (3 mg/kg i.p.) on Extracellular Levels of Monoamines in the Rat Prefrontal Cortex Dopamine Norepinephrine *=P<0.05 versus baseline * * 50 Methylphenidate 0 3 mg/kg i.p Time in hours From Bymaster et al., Neuropsychopharmacology,

5 Mechanism of Action MPH: Insights from PET Imaging Studies (Volkow et al. J Att Dis. 2002;(suppl)1) Because DA enhances task-specific neuronal signaling and decreases noise, MPH-induced increases in DA could improve attention and decrease distractibility Since DA modulates motivation, the increases in DA would also enhance the saliency of the task facilitating the interest it elicits and thus improving performance

6 Methylphenidate (Concerta) Increases dacc & DLPFC fmri Activation in ADHD during MSIT DLPFC Dorsal ACC DLPFC VLPFC Superior Parietal Cortex Bush et al. AGP Concerta (N=11) vs Placebo (N=10) 6

7 In ADHD Stimulants Found to Improve Core Symptoms AND Inattention Impulsivity Hyperactivity Noncompliance Impulsive aggression Social interactions Academic efficiency Academic accuracy ADHD Practice Parameters. JAACAP 1997;36:85S. Zametkin and Ernst. N Eng J Med 1999;340:40. 7

8 Weekly T-Score ADHD and Methylphenidate: Dose Effects on Attention in Clinic and Classroom CPT ADHD Comprehensive Teachers Rating Score % Academic Efficiency % On Task 15 placebo Methylphenidate Dose Rapport, et al. 1987

9 Indirect Effects of Medication on Parents, Teachers and Peers (Barkley et al., Cunningham et al.) Social changes in Parents and Teachers (Barkley et al., Pelham et al., Whalen et al.) Decreased rate of commands and degree of supervision Increased praise and positive responsiveness Social changes in Peers (Cunningham et al., Whalen et al.) Decreased negative and aggressive behavior on stimulants Leads to greater acceptance by peers Leads to further positive benefit to the child

10 MTA Study: Treatment Arms Medication management only - MPH tid, adjusted for best dose, other drugs if necessary; algorithmic dose adjustments; general advice and readings; case management by pharmacotherapist Intensive behavioral treatment only - Parent training; structured teacher consultation; 8-week, full-time summer treatment program; 12 weeks of half-time, classroom, behavioral specialist; case management by therapist/consultant Medication management + behavioral treatment (combined) Community-based care - After assessment by investigators, parents could seek community care (roughly 2 of 3 received medication) MPH=methylphenidate. MTA Cooperative Group. Arch Gen Psychiatry. 1999;56:

11 Average Score Average Score MTA: Treatment Effects on Inattention Scores (SNAP) [MTA Group, Arch General Psychiatry, 1999] CC Beh MedMgt Comb 3 Parent 3 Teacher Assessment Point (Days)

12 Average Score Teacher SSRS Social Skills CC Beh MedMgt 1.2 Comb Assessment Point (Days)

13 Average Score Parent-Child Arguing Time x Tx: F=5.6, p<.0008 Site x Tx: F=1.0, ns Site: F=2.8, p<.02 Comb, Beh > CC Assessment Point (Days) CC Beh MedMgt Comb

14 Effectiveness Factors in MTA Randomized Treatment Groups on Meds MedMGt CC Group t value P Variable (n=131) (n=94) Severity 52.4(17.4) 51.1 (16.6) NS CTQ-Total % Time on 89.0 (28.3) 41.1 (39.7) <.0001 MPH Average 2.9 (0.4) 2.1 (0.6) <.0001 doses/day Total Daily 32.8 (12.9) 18.7 (12.8) <.0001 Dose Total Visits 10.3 (4.3) 2.7 (3.5) <.0001 Months on MPH 9.9 (3.9) 5.5 (5.4) <

15 N=303 NIMH Preschool ADHD Treatment Study (PATS): Study Results MPH given tid decreased ADHD symptoms in a dose-dependent fashion Effect size was lower than observed in school-age children - dose was limited for safety reasons Rates of adverse events were higher and were different - e.g., crying, irritability, outbursts were very common Kollins S, et al. JAACAP. 2006;In press.; Greenhill LL, et al. JAACAP. 2006;In press. 15

16 ADHD Stimulant Dosing Medication Starting Dose Maximum Dose Usual Dosing (h) Methylphenidate Ritalin 5 mg QD/BID 2 mg/kg/day TID (4 hr) Focalin 2.5 mg 1 mg/kg/day BID (5-6hr?) Concerta 18 mg QD 2 mg/kg/day Once (12h) MetadateCD 10 mg QD Once (8-10h) Ritalin LA 10 mg QD Once Focalin XR 5 mg QD 1 mg/kg/day Once MTS patch 10 mg Once Quillivant XR 20 mg Once Amphetamine Adderall 2.5 to 5 mg QD 1.5 mg/kg/day BID (6 hr) AdderallXR 5-10 mg QD (12 hr) Dexedrine 2.5 to 5 mg QD 1.5 mg/kg/day BID/TID (4hr) Dex Spansule 5 mg BID (6 hr) Vyvanse mg 1 mg/kg/day Once (Wilens, Spencer, Biederman, Ann Review Medicine 53:2002)

17 Long Acting MPH formulations

18 Bioavailability from two MPH extended-release formulations. Gonzalez et al. Int J Clin Pharmacol Ther 40(4):

19 Classroom Study with two MPH ER formulations. Swanson et al. The Comacs Study. Pediatrics 2004;113:E206-E16

20 Conc (ng/ml) MPH ER Individual PK Plots Time (hrs)

21 Dexmethylphenidate H H H N 2 2 N H CH 3 OOC 2 Ph 2 Ph CHOOC 3 H H D (+) Methylphenidate (2R, 2 R) l (-) Methylphenidate (2S, 2 S) 21

22 DexMPH XR: Math Performance 22

23 Mean Change Score MTS Patch: Analog Classroom Mean Change from Pre-Dose in SKAMP Attention Scores Placebo Time (hr) Patch applied * MTS * * P <.001 MTS vs. placebo at all post-dose time-points. * * * * * Patch removed * 23

24 Pharmacological Dissociation Between The Robust Effects Of Methylphenidate On ADHD Symptoms And Weaker Effects On Working Memory Biederman et al. Eur Neuropsychopharmacol 2011

25 Meta-analysis of Within-Subject Comparative Trials Evaluating Response to Stimulant Medications Spencer et al. Arch of Gen Psych studies N=274 52% Best Response (Percent) % 23% 10 0 Dextroamphetamine Methylphenidate Equal response to either stimulant 25

26 PERMP Number Correct MAS XR Efficacy: Academic Productivity Randomized, Double-Blind, Placebo-Controlled Study Number of Math Problems Completed Correctly N = 49 Placebo MAS 10 mg MAS XR 10 mg MAS XR 20 mg MAS XR 30 mg Time Postdose (h) McCracken JT, et al. J Am Acad Child Adolesc Psychiatry. 2003;42(6):

27 Adderall XR Study in Youth with ADHD: CGIS-T Mean Total Score Afternoon * * * ITT Population Baseline Endpoint Change Placebo -5.4 Add XR 10 mg Add XR 20 mg Add XR 30 mg *P<0.001 (Dunnett test compared to placebo following ANCOVA with baseline score as covariate) (Biederman et al., Pediatrics 2003) 27

28 LDX Chemistry H N 2 O N H CH 3 H N 2 O OH H N 2 CH 3 Site of cleavage NH 2 NH 2 LDX l-lysine d-amphetamine 28

29 LDX Extraction, Pharmacokinetic and Abuse Liability Studies: Results Amphetamine is very difficult to extract from LDX prodrug Intravenous administration does not result in appreciable serum amphetamine levels in rat and human studies Intranasal administration does not result in appreciable serum amphetamine levels in rat and human studies Apparent saturation of LDX in gut limits ultimate serum amphetamine levels (e.g., overdose implications) Marginally less likeability in human studies Jasinski D, et al. Posters presented at CPDD Meeting, June, 2006, Scottsdale, AZ.; Biederman J, et al. Poster presented at Annual APA Meeting, May 24, 2006, Toronto, Ontario, Canada. Boyle L, et al. Presented at NCDEU, June 12-15, 2006, Boca Raton, FL.

30 ADHD-RS Total Score Pediatric LDX Study Primary Efficacy Endpoint: ADHD-RS ADHD-RS: ITT Population at End Point Placebo 30 mg 50 mg 70 mg N = * * * -40 *P<.0001 Baseline End Point Change (LS Mean) (adjusted Dunnett s test compared with placebo following ANCOVA with baseline score as covariate). 30

31 LS Mean SKAMP Score LDX : Duration of Action SKAMP Time Course LDX Adderall XR Placebo N= * * * * * * * ** ** ** ** ** ** ** Postdose (h) *P <.0001, **P <.01, LDX and Adderall XR vs placebo; LS = Least Square.

32 Change in ADHD-RS Total Score ADHD-RS Total Score LDX in Adult ADHD: ADHD-RS Total Scores (ITT Population) Placebo mg/d LDX 50 mg/d LDX 70 mg/d LDX -16.2* -17.4* -18.6* Baseline Endpoint Change from baseline (LS mean ± SE) A more negative change in ADHD-RS total score indicates greater improvement. LS=least squares; SE=standard error of the mean. *P<.0001 (adjusted Dunnett s test compared with placebo following ANCOVA with baseline score as covariate).

33 Effect Size Stimulant Tx of Executive Function Lisdexamfetamine in Adult ADHD + GEC > 65 Adler et al. JCP

34 Adverse Effects of Stimulants Adverse effects (AEs) are similar for all stimulants - Decreased appetite - Insomnia - Headache - Stomachache - Irritability/rebound phenomena Rates of these Aes may be high prior to any medical intervention; thus, baseline levels should always be obtained Wilens T, Spencer T. In: Child and Adolescent Psychiatric Clinics of North America. Philadelphia, Pa: Saunders Press; 2000:

35 Blood Pressure and Heart Rate Over 10 Years in the MTA No significant treatment-by-time effect was observed on systolic or diastolic blood pressure. A significant treatment-by-time effect was observed on heart rate (p=0.02), with significantly higher mean heart rates in the groups receiving medication at 14 months, but not afterward. (Vitiello et al. JAMA 2012)

36

37 Screening for Cardiac Risk: AHA Guidelines Medical history Personal congenital or acquired cardiac disease history Family history of cardiac disease (<50 years of age) Palpitations, chest pain, fainting, seizures, post-exercise symptoms Ask about other medications (including OTC) Routine medical exam Monitor BP and pulse at baseline and follow-up, especially in adults ECG is reasonable but not mandatory Routine check of Holter, ECHO is not necessary Gutgesell H, et al. Circulation. 1999:99: Schubiner H, et al. J Atten Disord. 2006;10:

38 Growth Velocity Z Scores Growth Over Time in Children Treated With MPH 1 Boys (n = 68) Girls (n = 16) Year Prior to Tx First Year Tx Second Year Tx Third Year Tx Duration of Tx 38 Lisska MC, Rivkees SA. J Pediatr Endocrinol Metab. 2003;16:

39 Onset of Tic Disorders in ADHD Probands Stratified by Stimulant Treatment Stimulant Treated Not Stimulant Treated Age in Years (Spencer et al., Arch Gen Psych, 1999)

40 Feel an Effect Feel an Effect (average±sem) 25 IR-MPH OROS-MPH Spencer, Biederman et al. Am J Psych a a a b a a p < 0.05 b P < Time (hrs)

41 Stimulant Medication and Substance Use Outcomes: A Meta-analysis Humphries et al. JAMA Psychiatry 2013

42 Characteristics of Diversion and Misuse of Medication in ADHD: Misused Prescribed Medication All with conduct or substance use disorders All with immediate-release not extended-release stimulants % p= % 10 2% 0 ADHD (N=55) Control (N=43) (Wilens, Gignac, Biederman et al., JAACAP 2006)

43 Protective Effect of Stimulants on Comorbidity 2 (1) = 19.7, p < (1) = 17.8, p < (1) = 3.5, p = Biederman et al. Pediatrics

44 Protective Effect of Stimulants on Comorbidity 2 (1) = 1.3, p = (1) = 21.4, p < (1) =1 9.9, p < Biederman et al. Pediatrics

45 Protective Effect of Stimulants 2 (1) = 18.4, p < Biederman et al. Pediatrics

46 Psychostimulant Treatment and the Developing Cortex in ADHD 46 Shaw et al 2009

47 Summary: Pharmacotherapy of ADHD Efficacy primarily documented in Caucasian boys Positive findings in adolescents and adults Preschoolers - variable response A variety of effective drugs Commonality: dopaminergic or noradrenergic mechanism of action 47