Lecture presented as part of an ADHD symposium at Walsh University in North Canton, OH on April 16, 2008. The lecture was sponsored by Mercy Medical Center and the Child and Adolescent Service Center of Stark County
For questions or further information, feel free to contact Dr. Grcevich at: Family Center by the Falls 8401 Chagrin Road, Suite 14B Chagrin Falls, Ohio 44023 Phone: 440.543.3400 E-mail: firstname.lastname@example.org For information about the Special Needs Ministry, please contact: Rebecca Hamilton, Executive Director Key Ministry Foundation 8401 Chagrin Road, Suite 14B Chagrin Falls, Ohio 44023 Phone: (440) 708-4488 E-mail: email@example.com www.keyministry.org
Revised TMAP Algorithm for Pharmacotherapy of ADHD References: 1. Pliszka SR, et al. J Am Acad Child Adolesc Psychiatry. 2006; 45(6) 642-657. 2. Pliszka SR, et al. J Am Acad Child Adolesc Psychiatry. 2003; 42 279-287.
The purpose of this slide is to provide physicians with a mental model for selecting an initial medication for ADHD.
Stimulants are the accepted firstline treatment for ADHD, but there are currently 19 approved stimulant products. On what basis does a physician choose from among these 19 products?
Stimulant Medications Indicated for ADHD Amphetamine sustained-release (SR) = Dexedrine Spansules Table not inclusive of all products
Differential Response to Stimulants Studies comparing stimulant medications have demonstrated comparable efficacy. However, there is much individual variability in response to a particular psychostimulant. This slide shows results of a meta-analysis of 6 controlled within-subject comparisons of AMP and MPH. Of the 174 subjects, 28% responded best to AMP, 16% responded better to MPH, and the remaining 41% responded equally well to either stimulant. No absolute predictors of response have been identified.
Implications of Arnold Study Many physicians may develop a “don’t rock the boat” approach to treatment of ADHD if they obtain even a modest positive response to initial treatment. These data appear to suggest that significant therapeutic benefit may result from trials with alternative stimulants, particularly in patients whose functioning has not normalized. With most chronic conditions, physicians will try to optimize treatment as much as possible. Why not with ADHD? Given the long-term course of the disorder, patients who experience a less than optimal response to an initial trial of stimulant medication deserve at least a brief trial with an alternative stimulant from the other subcategory so that preferential responders may be identified.
Faraone 2006 Metanalysis A recent meta-analysis of 29 double-blind, placebo-controlled, studies over the past 25 years in which the ADHD-RS was employed as a primary outcome measure suggests that stimulants are significantly more effective than non-stimulants in treating ADHD in pediatric patients. The studies enrolled a total of almost 4500 children and adolescents aged 8 to 15 years.
Atomoxetine (ATX) vs. OROS MPH This was a randomized, placebo-controlled study designed to show the “noninferiority” of atomoxetine (ATX) to Oros MPH in the treatment of ADHD in school age children. A 6-week blinded period was followed by an open label study, in which partial responders could be titrated to higher than approved doses (as high as 2.0 mg/kg/day), and patients optimized on higher doses were placed on reduced doses. Mean ATX dose was 1.45 mg/kg/day Mean OROS MPH dose was 39.9 mg/day 60% of patients enrolled had no prior stimulant treatment (N=516) In the long term study, increases in ATX dose did not result in additional benefit, and reduction in dose did not reduce the therapeutic benefit of the drug. In this study, ATX could not be shown to be “noninferior” to OROS MPH
This slide shows the mean change from baseline in the number of math problems attempted and completed correctly by hour. The values are the average of all analog classroom days (days 7, 14, and 21; weeks 1, 2, and 3). Subjects receiving Adderall XR ® attempted and correctly completed significantly more math problems at each time point postdose than subjects receiving Strattera ® (* P <0.0001 and ** P <0.05 for Adderall XR ® compared with Strattera ® for both number attempted and correct [ANCOVA]). Note: For each medication group, the change in the number of problems attempted and answered correctly was significantly improved compared with baseline at each time point postdose ( P <0.0001 by 1-sample t test).
This slide shows the difference between transdermal MPH and placebo and between OROS MPH and placebo on the ADHD-RS.
For example: MAS-XR in adolescents is approved in doses up to 20 mg/day (approved doses in children 6-12 range to 30 mg/day), despite the fact that randomized studies of doses up to 60 mg/day were submitted to the FDA, and a dose optimization study done as part of a Phase III trial indicated that for 63% of subjects, optimal dose was 30 mg/day or higher. Grcevich S et al. Presented at the 51 st Annual Meeting of the American Academy of Child and Adolescent Psychiatry, Washington DC, October 20, 2004.
Dr. Steinhoff’s study demonstrated that medication adherence was significantly improved among patients taking once-daily OROS vs. immediate-release MPH requiring multiple daily doses.
Maximum Change in Subject Liking Scores after LDX Oral Administration LDX was designed to have comparable efficacy and tolerability to that of once daily extended-release stimulants used in treating ADHD, but with reduced potential for abuse, diversion, and overdose toxicity. In trials to evaluate abuse liability, conducted among adults with a previous history of stimulant abuse, oral and intravenous LDX in doses comparable to or greater than d -amphetamine tended to be “less euphoric and more dysphoric” than d -amphetamine, with a later peak effect. Overall, doses of LDX were well tolerated. Asked which drug they would take again, d -amphetamine was preferred over LDX.1Similarly, a “likeability” study showed a lesser degree of subjective and behavioral effects in LDX vs. d -amphetamine at doses of 50 mg and 100 mg. At 150 mg of LDX, likability was comparable to d -amphetamine with a delayed peak effect.2The studies found that the biologically inactive prodrug attenuates the onset and intensity of amphetamine-like effects. References: Jasinski D, Krishnan S. Abuse liability of lisdexamfetamine dimesylate (LDX; NRP104). Presented at the US Psychiatric & Mental Health Congress, New Orleans, November 2006. 2. Jasinski D, Krishnan S. A double-blind, placebo- and active-controlled, 6-period crossover study to evaluate the likability, safety, and abuse potential of lisdexamfetamine dimesylate (LDX) in adult stimulant abusers. Presented at the US Psychiatric & Mental Health Congress, New Orleans, November 2006.
Filing for approval of SPD-465 (three-bead MAS-XR preparation) submitted to FDA 7/21/06. Filing for approval of SPD-503 (extended release guanfacine) submitted to FDA 8/24/06. One hypothesis as to why patients (and parents) often describe subjectively that stimulant duration of effect is shorter than effect described in randomized trials: The greater the change in PERMP performance between peak performance and the end of the day, the greater the likelihood patients will reports medication effects wear off too soon. Patients will “feel” more different at end of day, compared to peak. Least change occurs with OROS MPH, most with d-MPH XR. Effects of transdermal MPH increase as day progresses (dependent upon wear time). Differences in pharmacokinetics undoubtedly play a role as well.
These graphs show pooled results for the changes from predose in the number of math test problems attempted (left graph) and the number of math test problems correctly solved (right graph) over 12 hours of treatment with either d-MPH XR or placebo, where higher scores indicate an improvement. Treatment with d-MPH XR resulted in a significantly greater number of math problems attempted when compared with placebo at all time points ( P <0.001). Similarly, children taking d-MPH XR correctly solved a significantly greater number of math problems compared with those taking placebo at all time points ( P <0.001). Reference Turnbow JM, Muniz R, Lopez FA, et al. Once-daily dexmethylphenidate in children with ADHD: onset and duration of action in a laboratory classroom setting. Poster presented at: 18th Annual Meeting of the US Psychiatric and Mental Health Conference; November 7-10, 2005; Las Vegas, Nev.
The academic productivity measures depicted here represent the number of math problems completed in 10 minutes. Data are pooled numbers of all doses used. A significant difference was found between OROS MPH and placebo at all time points except for the first classroom period. The next available measure (classroom period) is 2 hours after dosing. This study showed OROS MPH displayed efficacy up to 12 hours post dose. Both active drug regimens were well tolerated.
Analog Classroom Study of Transdermal MPH: Impact on Math Performance Placebo-controlled studies of transdermal MPH show that the patch is well tolerated and results in significant improvement in classroom behavior and performance.1,2 The data above show that the patch improved classroom performance, as measured by math problems attempted and completed correctly. The treatment has also been shown to improve behavioral symptoms of ADHD as rated by the Swanson, Kotkin, Agler, M-Flynn, and Pelham Rating Scale deportment (SKAMP-D). Data presented at the annual meeting of the American Academy of Child and Adolescent Psychiatry in October 2006 showed improvements in symptoms when the patch was worn for 4 to 6 hours. References: 1. Wigal SB, et al. Poster presented at American Academy of Child and Adolescent Psychiatry Annual Meeting, Toronto, Canada, October 2005. 2. McGough JJ, Wigal SB, Abikoff H, et al. A randomized, double-blind, placebo-controlled, laboratory classroom assessment of methylphenidate transdermal system in children with ADHD. J Atten Disord . 2006;9:476-485.
Most clinicians will initiate treatment for ADHD first, unless symptoms of depression are severe, suicidal thoughts/plans are present, or psychotic features are present with depression. In many instances, the functional impairment associated with untreated/inadequately treated ADHD may be a predisposing/perpetuating factor contributing to depressed mood. There is no evidence to support efficacy of stimulant medication or atomoxetine in treating depression in children and adolescents.
Optimizing Medication Treatment in Children, Adolescents and Adults with ADHD
Optimizing Medication Treatment in Children, Adolescents and Adults with ADHD Stephen Grcevich, M.D. CWRU School of Medicine, Cleveland, Ohio Family Center by the Falls, Chagrin Falls, OH Presented at: Barrett Business and Community Center Walsh University North Canton, Ohio April 16, 2008E-mail: firstname.lastname@example.org Web: www.fcbtf.com Phone: 440.543.3400Special Needs Ministry: www.keyministry.org
Objective: Equip participants with anevidence-based model to guideprescribing decisions for ADHD patients To meet this objective, participants will: Review current practice parameters and recommended strategies for initiating ADHD pharmacotherapy Explore a systematic approach for optimizing treatment of individual patients with ADHD Discuss treatment strategies for ADHD patients with comorbid conditions Medication uses not currently approved by the FDA will be discussed Brand names may be used during the presentation for purpose of clarity
Potential Conflicts of Interest: (Complete disclosure for 2006-08 available at www.fcbtf.com)Source of conflict: Company:Consultant: Shire US (2006, 2007)Grant/research support: No current ADHD research supportMajor shareholder: N/AOther financial/material Independent Contractor: Medscape Consultant: MEDACorp/ Leerink-support: Swann, Porter NovelliSpeakers’ bureau: Shire US (through March, 2006) None in last 24 months
Revised TMAP* Algorithm for Pharmacotherapy of ADHD Consensus conference of academic clinicians and researchers, practicing clinicians, administrators, consumers, families Revised algorithms based upon new research developed for treatment of ADHD, with and without common comorbid conditions Children treated according to earlier algorithms achieved better outcomes and were exposed to less polypharmacy than controlsTMAP=Texas Medication Algorithm Project*Pliszka 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: What’s the best drug (molecule) for the patient? Do they respond best to AMP or MPH? What’s the best dose for them? Are you giving them enough to get the desired result? What’s the necessary duration of action? Does the medication work when it needs to later in the day? And the best delivery system? When do you most need the peak effect from medicine? What are they least likely to misuse? What if they can’t swallow pills?Grcevich S. Future Neurology 2006; 1(5) 525-534
Factors in Selecting Medication for Individual ADHD Patients:Other Considerations: TMAP suggests amphetamine (AMP) or MPH as first-line Rx, but which one? Side effect/safety issues CostPliszka SR et al. J Am Acad Child Adolesc Psychiatry 2006;45(6):642-657.
Differential Response to Stimulants Meta-Analysis of Within-subject Comparative Trials Evaluating Response to Stimulant Medications 50 40 Best 41%response 30(percent) 28% 20 10 16% 0 AMP MPH Equal response to either stimulantAMP=amphetamineMPH=methylphenidate Arnold et al. J Attention Dis 2000;3:200-211.
Implications of Arnold Study: Patients with uncomplicated ADHD should receive a trial of an alternate stimulant molecule if they fail an initial trial Suboptimal responders (improved, but not normalized) to a given stimulant may benefit from an alternative stimulant Problem: Physicians are often reluctant to increase medication dose or consider alternative molecules when results are less than optimal
Atomoxetine (ATX) vs OROS-MPH 70 60Percent Response 50 to Treatment 40 30 ATX OROS 20 10 0 Prior Tx. Naïve Total Stim Sample Michelson, D. Presented at AACAP Annual Meeting, Washington, DC, October 21, 2004
Math Problems by Hour (ITT) MAS-XR vs. Atomoxetine MAS XR® Change in Attempted ATX Change in Attempted MAS XR® Change in Correct ATX Change in Correct 80 75.6* 77.2*Change in Number of Math Questions 70.1* 79* 70 75* 67.5* 72.3* 68.4* 56.8* 60 56.9* 50 40.7 40 34.2 36.3 44.6 31.9 35.1 38.4 30 23.3 34.3 20 24.0† 13.7 16.6 18.6 10 12.1 0 0 2 4.5 7 9.5 12 Time (hr) *P<0.0001 MAS XR® compared with ATX for both number attempted and correct (ANCOVA); †P<0.05 for number attempted. Wigal SB et al. J Atten Disord 2005; 9(1) 275-289
Studies Comparing d- and L-AMP: Arnold (1976)-randomized, crossover study (N=31): d- and L- isomers are equally efficacious, (non-significant trend toward d-AMP > L-AMP)-trend toward L-AMP more effective in “undersocialized, aggressive” children. 28% of drug responders preferred L-AMP James (2001)-randomized, crossover study (N=35) comparing d-AMP IR, d-AMP ER, MAS- IR. MAS-IR produced most robust effects in AM, only d-AMP improved cognitive performance in analog classroom after 4 hours Biederman (2006) LDX vs. MAS-XRArnold LE et al. Arch Gen Psychiatry, 1976;33(3):292-301 JamesRS 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: MPH Patch OROS MPH Placebo 0 -5 Mean Change Scores -10 -15 -10.3 -20 -25 -21.6 * -24.2 -30 * -35 -40 -45 -50 Change from Baseline* 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
Dosing Issues FDA marketing guidelines for new products reflect smallest possible effective dose, not optimal dose FDA doesn’t take into account variability in dose response between individual patients when determining approved dose Open-label or dose-optimization studies often suggest higher-than-approved doses are beneficial for individual patients Notion of ‘approved’ vs ‘clinical’ dose in practice parameters Response to stimulants is highly individualized
Selecting the Right Delivery System: Can the person swallow pills? Risk of drug diversion, abuse How soon does the product work? When does maximum benefit occur? How often do you need to administer? (Increased frequency=decreased adherence)Steinhoff K et al. Presented at 53rd Annual Meeting of AACAP, San Diego, CA, October 27, 2006
Maximum Change in Subject Liking Scores after LDX Oral Administration 6 Placebo * Mean Maximum Change 4.9 5 LDX 100 mg in DRQ-S Scores d-amphetamine 40mg 4 3 2.6 † 2 1 0.4 0 Treatment 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.
Duration of Action Extracurricular activities, homework, driving render concept of school- or work-day coverage obsolete Why do patients tell you XR stimulants don’t last as long as they should? Every ADHD product currently issued “approvable” letter lasts at least as long (if not considerably longer) than the products they are intended to replace
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 * * 70 * 70 * * Mean Change From Predose, * * Mean Change From Predose, * * * 60 * * 60 * * * 50 * Improvement 50 * *Improvement * * Math Attempted 40 40 Math Correct * 30 * 30 * * 20 * 20 * 10 10 0 0 -10 -10 -20 -20 -30 -30 0 0.5 1 2 3 4 5 6 7 8 9 10 11 12 0 0.5 1 2 3 4 5 6 7 8 9 10 11 12 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 40 Transdermal * * * 35 30 MPH * * * Mean Change Score 25 * 20 Improvement 15 * * P < .001 Transdermal MPH vs 10 placebo at all measured post-dose 5 time points. 0 -5 -10 -15 Placebo -20 0 1 2 3 4 5 6 7 8 9 10 11 12 Time (hr) 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: Dose DeliveryProduct: Molecule: Range: Duration: System: Advantages: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 4 Scahill L, et al. Am J Psychiatry. 2001;158:1067–1074.
Comorbidity: A Diagnostic Consideration Lifetime Prevalence of Comorbid Conditions in Pediatric Population With ADHD Boys (N = 140) 70 66 Girls (N = 140) 60 50 40 35 % 32 33 29 30 25 28 21 20 15 11 11 10 8 0 Major Multiple Conduct Bipolar ODD Enuresis Depression Disorder Disorder (>2) AnxietyBiederman J. J Clin Psychiatry. 2004;65(suppl 3):3-7.
TMAP Algorithm: Pharmacologic Management of ADHD and Comorbid Depressive DisorderPliszka SR et al. J Am Acad Child Adolesc Psychiatry 2006: 45(6) 642-657
TMAP algorithm for pharmacologic management of ADHD and comorbid anxiety disorder: Pliszka SR et al. J Am Acad Child Adolesc Psychiatry 2006: 45(6) 642-657
TMAP algorithm for pharmacologic management of ADHD with comorbid tic disorder: Pliszka SR et al. J Am Acad Child Adolesc Psychiatry 2006: 45(6) 642-657
Bottom line: What is most important toyou as physician, to the parent/patient? Efficacy: AMP (slight advantage)>MPH>ATX Duration of action: Transdermal MPH (with extended wear time)>OROS MPH=LDX> MAS- XR>d-MPH XR Flexible duration: Transdermal MPH Rapid onset: IR stimulant>d-MPH XR>OROS MPH>Transdermal MPH Abuse Potential: ATX, evidence for less abuse potential with LDX, OROS-MPH, transdermal MPH, indirect evidence of less abuse potential with other ER stimulants
Conclusions: Optimizing treatment for individual patients with ADHD is likely a critical factor in improving treatment adherence Key considerations for each patient include: identifying the molecule they respond to optimally (drug), prescribing an adequate dose to normalize symptoms, treating functional impairment all day long (duration), and using the best delivery system to provide peak effects when necessary while improving adherence