Common Sense Strategies For Prescribing ADHD Medication

E-mail: drgrcevich@fcbtf.com Web: www.fcbtf.com Phone: 440.543.3400Special Needs Ministry: www.keyministry.org

Objective: To help participants developan evidence-based model to guideprescribing decisions for individualpatients with ADHD To meet this objective, participants will:

Capone NM, McDonnell TP. Presented at the APA Annual Meeting, Toronto, ON (2006)

More Frequent Office Visits May Help ADHD Medication Adherence A B Patients (%) Patients (%) Office Visits ADHD Rxs Filled Data shown are the rate (%) of patients with the indicated number of office visits or prescriptions filled over the 12-month study period.Grcevich S, et al. Presented at: AACAP Annual Meeting, San Diego, CA, October 27, 2006.

Monthly Persistence With OROS-MPH (N=2398) % of PatientsCapone N, et al. Presented at the CHADD International Conference (2005) Dallas, TX.

Monthly Persistence With MAS-XR (N=1626) 100% 90% 80% 70% % of Patients 60% 50% 40% 30% 20% 10% 0% Sep-03 Oct-03 Nov-03 Dec-03 Jan-04 Feb-04 Mar-04 Apr-04 May-04 Jun-04 Jul-04 Aug-04 MAS-XR CategoryCapone N, et al. Presented at the CHADD International Conference (2005) Dallas, TX.

Monthly Persistence With ATX (N=1292) 100% 90% 80% 70% % of Patients 60% 50% 40% 30% 20% 10% 0% Sep-03 Oct-03 Nov-03 Dec-03 Jan-04 Feb-04 Mar-04 Apr-04 May-04 Jun-04 Jul-04 Aug-04 ATX CategoryCapone N et al. Presented at the CHADD International Conference, Dallas, 2005.

Grcevich S, et al. Presented at: AACAP Annual Meeting, San Diego, CA, October 27, 2006.Wolraich ML, et al. Pediatrics. 2005;115:1734-1746.

*TMAP=Texas Medication Algorithm ProjectPliszka SR, et al. J Am Acad Child Adolesc Psychiatry. 2006;45:642-657.Pliszka SR, et al. J Am Acad Child Adolesc Psychiatry. 2003;42:279-287.

Algorithm for the Pharmacological Treatment of ADHD (with no significant comorbid disorders), Revised 2005 Pliszka SR, et al. J Am Acad Diagnostic Assessment and Family Child Adolesc Psychiatry. Stage 0 Consultation Regarding Treatment 2006;45:642-657. Alternatives Non-MedicationAny stage(s) can be skipped Treatment Alternativesdepending on the clinical picture Stage 1 Methylphenidate or Amphetamine Response Stage 1A Partial (Optional) Response Response (if MAS or Formulation not DEX used used in Stage 1 Continuation Partial Response in Stage 1) or Non-response Partial Response or Non-response Stage 2 Stimulant not used in Stage 1 DEX = Dextroamphetamine MAS = Mixed amphetamine salts

Pliszka SR, et al. J Am AcadStage 2 Stimulant not used in Stage 1 Child Adolesc Psychiatry. 2006;45:642-657. Response Stage 2A Partial (Optional) Response Response Continuation Formulation not (if MAS or used in Stage 2 DEX used in Stage 2)Stage 3 Partial Response Partial Response or Non-response or Non-response Atomoxetine Response Stage 3A Partial (Optional) Response Response Combine stimulant Continuation to stimulant or atomoxetine and atomoxetine Partial Response or Non-response Partial Response or Non-responseStage 4 Bupropion or TCA TCA = Tricyclic antidepressant

Pliszka SR, et al. J Am Acad Child Adolesc Psychiatry.Stage 4 Bupropion or TCA 2006;45:642-657. Response Continuation Partial Response or Non-responseStage 5 Agent not used in Stage 4 Response Continuation Partial Response or Non-responseStage 6 Alpha agonist Clinical Consultation Maintenance

Factors in Selecting Medication for Individual ADHD Patients:Grcevich S. Future Neurology 2006; 1(5) 525-534Pliszka SR et al. J Am Acad Child Adolesc Psychiatry 2006;45(6):642-657.

Approved stimulant products for ADHD: Immediate- Long-Acting, Long-Acting, Release Formulated Non- Prodrug Stimulants Stimulants Stimulants Stimulants Lisdexamfetamine Amphetamine Amphetamine SR Atomoxetine dimesylate D- Dexmethylphenidate XR methylphenidate Methylphenidate Methylphenidate CD Mixed Methylphenidate LA amphetamine salts Methylphenidate patch Mixed amphetamine salts XR OROS* methylphenidate*OROS=osmotic release oral system

Faraone 2006 Metanalysis (29 controlled studies, 4465 children, adolescents)Amphetamine 0.92Methylphenidate 0.80Atomoxetine 0.73Modafinil 0.49Buproprion 0.32Faraone SV, Spencer TJ: Presented at APA Annual Meeting, Toronto, Canada (2006)

Percent Response to Treatment Michelson, D. Presented at AACAP Annual Meeting, Washington, DC, October 21, 2004

0.33† ‡ ‡ ‡ ‡ ‡ * –0.47† –0.74† –0.78† –0.81† –0.86† *P<0.05; †P<0.0001 compared with baseline by 1-sample t test. ‡ P<0.0001 MAS-XR compared with ATX by ANCOVA.Wigal et al. Poster presented at the 157th Annual Meeting of the American Psychiatric Association, New York, May 4, 2004.

Meta-Analysis of Within-subject Comparative Trials Evaluating Response to Stimulant Medications Best 41%response(percent) 28% 16%AMP=amphetamineMPH=methylphenidateArnold et al. J Attention Dis 2000;3:200-211.

Implications of Arnold Study:

Arnold LE et al. Arch Gen Psychiatry, 1976;33(3):292-301James RS et al. J Am Acad Child Adolesc Psychiatry 2001;40(11):1268-76

LDX vs. MAS-XR in Children:SKAMP LS Mean Across Assessment Day – ITT Population 3– – LDX *** p<0.001 compared to placebo – MAS-XR – 2– Placebo Mean Score – – – *** *** 1 – *** *** – – – 0– Deportment (primary endpoint) InattentionBiederman J. et al. Poster presented at Annual APA Meeting, May 24, 2006, Toronto, Ontario, Canada

OROS-MPH/MPH Patch Parallel Group Study: * ** P < .0001 vs placebo.Study was not powered for comparison between transdermal and OROS MPH.Findling and Lopez. Poster presented at the AACAP Annual Meeting. Toronto. Oct. 20, 2005. N=270

Selecting the Right Delivery System:Steinhoff K et al. Presented at 53rd Annual Meeting of AACAP, San Diego, CA, October 27, 2006

New Delivery Systems: LDX O! CH!3 O!H 2 N! H 2 N! N! OH! CH! 3 Rate-limited! H! + Hydrolysis ! H 2 N! Site of cleavage!NH!2 NH!2 Lisdexamfetamine l-lysine! d-amphetamine  (Prodrug) ! (active) !

Maximum Change in Subject Liking Scores after LDX Oral Administration Placebo * Mean Maximum Change LDX 100 mg in DRQ-S Scores d-amphetamine 40mg †   Oral administration of 150 mg of LDX produced increases in positive subjective responses that were statistically indistinguishable from the positive subjective responses produced by 40 mg of oral immediate-release d-amphetamineDRQ-S=Drug Rating Questionnaire-Subject.; *P<.01 vs placebo; †P<.05 vs d-amphetamineJasinski D, Krishnan S. Poster presentation at US Psychiatric & Mental Health Congress Annual Meeting,New Orleans, Nov 18, 2006.

Analog classroom study of d-MPH XR: Impact upon math performance Change From Predose in Number Change From Predose in Number of of Math Test Problems Attempted Math Problems Correctly Solved * * * * * Mean Change From Predose, * * Mean Change From Predose, * * * * * * * * * Improvement * *Improvement * * Math Attempted Math Correct * * * * * * Hours Postdose Hours Postdose All P values, d-MPH XR versus placebo. *P<0.001. Pooled data; Studies US08 and US09. Turnbow JM et al. US Psychiatric and Mental Health Conference; 2005; Las Vegas, NV

Analog classroom study of OROS MPH: Impact upon math performance Change in number of math problems completed 50 45 40 35 30 25 20 15 Placebo 10 OROS MPH (all doses) TID MPH (all doses) 5 0 8:15 9:20 10:30 12:30 14:05 16:00 17:15 18:20 19:10 Class period Pelham WE et al. Pediatrics 2001; 107(6) e105.

Analog Classroom Study of Transdermal MPH: Impact on Math Performance Laboratory Classroom Mean Change from Pre-Dose in Number of Math Problems Correct Transdermal * * * MPH * * * * Improvement * * P < .001 Transdermal MPH vs placebo at all measured post-dose time points. Placebo N=79 Patch applied Patch removedWigal et al. Poster presented at the AACAP Annual Meeting, Toronto, October 21, 2005.

Comparison of Frequently Prescribed Stimulant Preparations:MAS-XR d,l-AMP 5-30 Up to 12 Biphasic Rapid onset, mg/day hours release effective for ODD, adultsLDX d-AMP 30-70 12 hours Prodrug Less appeal to mg/day addicts, more consistent duration?OROS-MPH MPH 18-72 12 hours Osmotic Prolonged effects mg/day release on drivingD-MPH XR MPH 5-20 12 hours Biphasic Rapid onset mg/day (claimed) releaseTransdermal MPH 10-30 Variable, Patch Potentially longestMPH mg/day based on acting, most wear time flexible duration

Bupropion XL in Adults With ADHD: Percent Responders* 60 ** ** 50 † ** Bupropion XL (N = 81) Responders (%) 40 30 20 Placebo (N = 81) 10 0 1 2 4 5 8 Time in Study (wk) *≥30% reduction from baseline; **p≤0.01, †p<0.05Wilens T, et al. Biol Psychiatry. 2005;57:793-801.

Guanfacine in the Treatment of Children with Tic Disorders and ADHD Improvement in Outcome Measures Measure Guanfacine Placebo P- 0.5-4.5 (n =17) value mg/d (n =17) ADHD-RS total score 37% 8% <0.001 CGI Global Improvement Scale 47% 0% <0.001 (rated much improved or very much improved) Yale Global Tic Severity Scale total score 31% 0% 0.05   Double-blind, placebo-controlled, parallel design, 8-week study in 34 medication-free youths with ADHD plus tics; age 7-14   Guanfacine immediate release given TID; maximum allowable dose: 4mg/kg TID   No serious side effects observed; no clinically meaningful cardiovascular changes   One guanfacine discontinuation owing to sedation in week 4Scahill L, et al. Am J Psychiatry. 2001;158:1067–1074.

ADHD-RS: Mean Total Score at Endpoint and Change in LS Mean from Baseline (ITT Population) 40 ADHD-RS Total 30 Baseline Endpoint Score 20 Change in Least Square (LS) 10 0 Mean Change in ADHD-RS Total -10 Score -20 ** ** *** -30 Placebo 2 mg 3 mg 4 mg*8-week, double-blind, placebo-controlled, parallel-group safety and efficacy study; **p<..001; *** p<.0001 (adjusted Dunnett test compared to placebo following ANCOVA withbaseline score as covariate)Bear Stearns. Presented at London Healthcare Conference, London, March 2004.

Comorbidity: A Diagnostic Consideration Lifetime Prevalence of Comorbid Conditions in Pediatric Population With ADHD Boys (N = 140) Girls (N = 140) Major Multiple Conduct Bipolar ODD Enuresis Depression Disorder Disorder (>2) AnxietyBiederman J. J Clin Psychiatry. 2004;65(suppl 3):3-7.

Correlates of ADHD Among Childrenin Pediatric and Psychiatric Clinics Referral Site Psychiatric Pediatric (N=139) % (N=141) % CD 14 15 ODD 55 45 MDD 50 42 BPD 13 9 Anxiety disorders 33 29 (≥2) SUD* 13 15 Tics 10 *SUD includes cigarettes and psychoactive substances. 6Busch et al. Psychiatric Services. 2002;53:1103.

TMAP Algorithm: Pharmacologic Management of ADHD and Comorbid Depressive DisorderPliszka SR et al. J Am Acad Child Adolesc Psychiatry 2006: 45(6) 642-657

Pliszka SR et al. J Am Acad Child Adolesc Psychiatry 2006: 45(6) 642-657

TMAP algorithm for pharmacologic management of ADHD and aggression:Pliszka SR et al. J Am Acad Child Adolesc Psychiatry 2006: 45(6) 642-657

Common Sense Strategies For Prescribing ADHD Medication

by Stephen Grcevich, MD on Jan 01, 2012

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