Case Study Activity: Management of Attention-Deficit/Hyperactivity Disorder Answers to Interactive Questions Case 2: Dosing of Attention-Deficit/Hyperactivity Disorder Medications Activity Preview Optimization of dosing is crucial for obtaining the most therapeutic benefit from attentiondeficit/hyperactivity disorder (ADHD) medications. Finding the right dosing regimen for an individual patient involves titrating the dosage based on symptom assessment throughout the day with standardized rating tools (e.g., Conners Rating Scale). Guidelines recommend starting at the low end of the dosing range to allow for the possibility that a low dose could be effective. Initiating drug therapy at lower dosages also can help the patient tolerate adverse effects before increasing the dosage. According to some studies, implementing systematic behavioral interventions can result in ADHD symptom improvement at lower doses of stimulants. Other studies show that stimulants are sometimes deemed ineffective because the dosing is not increased appropriately. Patients need 1 week of objective assessment after starting stimulants at a given dose before titrating upward. Atomoxetine, bupropion, and extended-release preparations of clonidine or guanfacine should be given for at least 2 weeks before increasing the dosage because of the longer onset of therapeutic effect 2 to 4 weeks for these medications. Ensuring proper adherence to the prescribed regimen through pill counts, refill histories, and direct queries of patients and families is also necessary before dosage titration. TABLE 1 provides comparative information on stimulant product formulations and lists recommended starting doses, dosing ranges, and recommended maximum dosages. TABLE 2 gives dosing recommendations for 1
atomoxetine, bupropion, and immediate- and extended-release preparations of clonidine and guanfacine. Clinical trials evaluating different dosing strategies for stimulants in the treatment of ADHD have shown that immediate- release methylphenidate should be given three times a day for optimal symptom coverage while dexmethylphenidate, dextroamphetamine, and mixed amphetamine salts are longer acting and can be given twice daily in the morning and midday. Studies evaluating atomoxetine therapy suggest that twice-daily dosing in the morning and evening minimizes adverse effects compared with once daily-dosing, although the latter is tolerable in many individuals. Atomoxetine has been found to be less likely to adversely impact eating disorder behavior in patients. The goal dose for atomoxetine in youths is 1.2 mg/kg/day for an adequate therapeutic trial in most patients; doses up to 1.8 mg/kg/day may be required in adults. Approximately 5% to 10% of individuals are poor metabolizers of cytochrome P450 2D6 (CYP2D6) and they may have more adverse effects at lower dosages of atomoxetine. Clinical monitoring is needed to detect these individuals, as screening for CYP2D6 metabolism status is not routinely available. Extended-release α 2 -adrenergic agonists have U.S. Food and Drug Administration (FDA) approval as monotherapy or as add-on treatment to stimulant therapy for children and adolescents aged 6 to 17 years old. Studies show greater efficacy in younger, smaller children compared with older, heavier adolescents. Extended-release guanfacine is best given once daily, and extended-release clonidine should be administered twice daily for optimal therapeutic benefit. When the dose of stimulant has been optimized but is only partially effective, extendedrelease guanfacine or extended-release clonidine have been found to increase the therapeutic effects as measured on ADHD rating scales, according to several studies in youths. The addition of α 2 -adrenergic agonists to stimulant therapy brings the risk of additional adverse effects such as lethargy, fatigue, sedation, constipation, dizziness, and bradycardia. Due to α 2A -selectivity, guanfacine may cause less dizziness and sedation compared with clonidine. When discontinuing treatment with α 2 -adrenergic agonists, it is prudent to taper dosages for optimal tolerability and to minimize the risk of rebound hypertension. 2
The American Academy of Child and Adolescent Psychiatry s clinical practice guidelines on the treatment of ADHD recommend once-daily stimulant formulations over immediate-release stimulants given throughout the day due to more reliable symptom coverage, the avoidance of dosing at school, and improved adherence. Once-daily stimulant formulations differ in their delivery systems and percentage of immediate- and extended-release beads (TABLE 1). These differences translate to varying onsets of effect, duration of effect, and potential for abuse and drug diversion. The osmotic-release oral system (OROS) formulation of methylphenidate (Concerta) has a longer onset than the spheroidal oral drug absosrption system (SODAS) formulation of methylphenidate (Ritalin LA), but it provides for a longer duration of effect 12 with the OROS formulation versus the usual 8 to 10 with the SODAS formulation. The methylphenidate transdermal patch provides up to 12 of symptom coverage when the patch is worn for 9. Dextroamphetamine spansules provide 4 to 6 of symptom relief while extended-release mixed amphetamine salts provide up to 12 of symptom coverage for most individuals. Lisdexamfetamine requires gastrointestinal conversion to the active dextroamphetamine and therefore its onset of effect is longer than that of other amphetamine preparations. Its duration of effect may be longer as well, up to 14. Co-administration of stimulants with food can delay the onset of effect for immediate-release stimulant formulations and extended-release mixed amphetamine salts, but food does not significantly affect the onset of methylphenidate extended-release OROS formulation, methylphenidate transdermal patch, or lisdexamfetamine. It is necessary to maximize the dosage as tolerated before considering a medication ineffective. The Multimodal Treatment Study of Children with ADHD, which studied close to 600 7-to 10- year-old children with ADHD, found the average effective methylphenidate dose was approximately 33 mg per day. In another study in aggressive 6- to 13- year-olds with ADHD, investigators found that systematic weekly methylphenidate titration to an average dose of 52 mg per day along with behavioral therapy resulted in optimal symptom control without the need for medications to treat aggressive behavior such as risperidone or quetiapine. This approach prevents exposure to the risk of adverse effects associated with atypical antipsychotic medications such as weight gain, diabetes, hyperprolactinemia, and extrapyramidal symptoms. Studies in adolescents taking OROS methylphenidate documented that most of them needed 3
between 54 mg and 72 mg per day for optimal therapeutic benefit. Studies in adolescents and adults with ADHD show that doses of stimulant above the recommended daily maximum are frequently needed for optimal symptom control. These findings prompted the American Academy of Child and Adolescent Psychiatry to publish an off-label maximum dosage of 100 mg per day for methylphenidate and 60 mg per day for dextroamphetamine and mixed amphetamine salts. These dosage ranges appear in the Academy s clinical practice guidelines on the treatment of ADHD. 4
Case Study Jason B. is a 13-year-old boy with ADHD, combined type (i.e., hyperactive, impulsive, and inattentive symptoms present). His height is 5' 9" and weight is 145 lb (65.7 kg). Comorbid conditions include conduct disorder and asthma. Jason was diagnosed with ADHD at age 12; his parents implemented behavioral interventions such as positive rewards for good behavior and structured limit setting with minimal improvement in symptoms. Jason is struggling through his last year of middle school with a C average; his basketball coach noted that Jason exhibits overly aggressive behavior during practice. Current medications include montelukast 10 mg daily for 1 year and albuterol inhaler/nebulizer as needed for acute asthma attacks for 2 years. 5
Question 1 1. Which of the following is an appropriate starting dose of ADHD medication for Jason? a. Methylphenidate OROS 54 mg every morning. b. Extended-release dexmethylphenidate 5 mg twice daily. c. Extended-release mixed amphetamine salts 10 mg every morning. d. Lisdexamfetamine 20 mg twice daily with meals. Answer to Question 1 The correct answer is c. Extended-release mixed amphetamine salts 10 mg every morning is an appropriate starting dose for treating ADHD. Answer a is incorrect. TABLE 1 shows that 54 mg is too high for a starting dose of methylphenidate OROS. Answer b is incorrect. Dexmethylphenidate immediate-release is started at 5 mg per day, but the extended-release once-daily preparation is preferred according to guidelines. Answer d is incorrect because lisdexamfetamine is given once daily in the morning. Question 2 2. Jason s parents ask about the onset of therapeutic effect of the newly initiated stimulant medication. What counseling will you provide regarding how long to allow for assessing a given stimulant dose prior to increasing it? a. 1 week. b. 2 weeks. c. 2 to 4 weeks. d. 6 weeks. Answer to Question 2 The correct answer is a. Studies show stimulants have the most rapid onset of effect and their therapeutic benefit is observed within 1 week of an effective dose. 6
Answer b is incorrect; 2 weeks in too long to wait to assess the therapeutic effect. Answer c is incorrect; 2 to 4 weeks is the time to wait for assessing a dose of clonidine or guanfacine therapy. Answer d is incorrect; 6 weeks is the time for an adequate trial of antidepressant therapy. Question 3 3. Jason has been taking 30 mg per day of mixed amphetamine salts for 4 weeks now and his attention is better with improved behavior in the classroom. He is able to raise his hand before speaking. He is calmer and less aggressive, and his grades have improved to a B average. Unfortunately, significant symptoms remain as Jason is still impulsive, unable to wait his turn in line at basketball practice, and he has trouble completing homework assignments. He reports persistent insomnia and poor appetite. Select the most appropriate drug therapy adjustment to recommend to Jason s primary care physician. a. Increase mixed amphetamine salts to 40 mg in the morning. b. Add extended-release guanfacine 1 mg and titrate to response. c. Switch to atomoxetine 10 mg twice daily and titrate to response. d. Switch to immediate-release mixed amphetamine salts 20 mg twice daily. Answer to Question 3 The correct answer is b. Adding guanfacine could help Jason sleep at night, and it has been shown to enhance the effectiveness of stimulant treatment. Answer a is incorrect because increasing mixed amphetamine salts can result in more insomnia and poor appetite. The FDA-approved maximum recommended daily dosage is 30 mg/day. Answer c is incorrect because it is not time to give up on stimulant therapy; the atomoxetine starting dose is too low for Jason as well. 7
Answer d is incorrect because dividing the dose and increasing the total daily dose of mixed amphetamine salts will increase adverse effects. Question 4 4. Jason s 36-year-old mother has been treated for bulimia nervosa and depression for 2 years. Her height is 5' 7" and weight is 150 lb (68 kg). She is currently taking escitalopram 20 mg with remission of depressive symptoms but intermittent binging and purging remain. She is evaluated and diagnosed with ADHD. Recommend the most appropriate drug and dosing schedule for ADHD treatment in Jason s mother. a. Stop escitalopram; start bupropion 150 mg every morning to treat depression and ADHD. b. Start lisdexamfetamine 20 mg in the morning with titration weekly to response. c. Initiate atomoxetine 20 mg two times a day with meals and titrate every 2 weeks to response. d. Start extended-release guanfacine 1 mg daily with titration to therapeutic response. Answer to Question 4 The correct answer is c. Atomoxetine has been found to be effective for adult ADHD and it is the least likely agent to adversely affect eating disorder behavior. Answer a is incorrect. Bupropion is contraindicated in patients with eating disorders and it has not been shown to be as effective as other treatments for ADHD. Answer b is incorrect. Individuals with eating disorders should not be given stimulant medications. Stimulants can worsen eating disorder behaviors and increase seizure risk. Answer d is incorrect. Guanfacine has not been demonstrated effective for adults with ADHD. 8
References American Academy of Pediatrics, Subcommittee on Attention-Deficit/Hyperactivity Disorder, Steering Committee on Quality Improvement and Management. ADHD: clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics. 2011;128:1007 22. Blader JC, Pliszka SR, Jensen PS, et al. Stimulant-responsive and stimulant-refractory aggressive behavior among children with ADHD. Pediatrics. 2010;126:e796 e806. Brams M, Moon E, Pucci M, et al. Duration of effect of long-acting stimulant medications for ADHD throughout the day. Curr Med Res Opin. 2010;26:1809 25. Conners CK. Conners Rating Scales Revised (CRS-R). Available at: http://psychcorp.pearsonassessments.com/haiweb/cultures/enus/productdetail.htm?pid=pag116. Accessed 2/8/2012. Dopheide JA, Pliszka SR. Attention-deficit-hyperactivity disorder: an update. Pharmacotherapy. 2009;29:656 79. Ermer JC, Adeyi BA, Pucci ML. Pharmacokinetic variability of long-acting stimulants in the treatment of children and adults with attention-deficit hyperactivity disorder. CNS Drugs. 2010;24:1009 25. Greenhill LL, Newcorn JH, Gao H, et al. Effect of two different methods of initiating atomoxetine on the adverse event profile of atomoxetine. J Am Acad Child Adolesc Psychiatry. 2007;46:566 72. Newcorn JH, Stein MA, Cooper KM. Dose-response characteristics in adolescents with attention-deficit/hyperactivity disorder treated with OROS methylphenidate in a 4-week openlabel, dose-titration study. J Child Adolesc Psychopharmacol. 2010;20:187 96. Pliszka SR; American Academy of Child and Adolescent Psychiatry Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2007;46:894 921. Spencer TJ, Greenbaum M, Ginsberg LD, et al. Safety and effectiveness of coadministration of guanfacine extended release and psychostimulants in children and adolescents with attentiondeficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2009;19:501 10. Wigal SB, Gupta S, Heverin E, et al. Pharmacokinetics and therapeutic effect of OROS methylphenidate under different breakfast conditions in children with attentiondeficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2011;21:255 63. 9
Table 1. Stimulant Drugs Used in the Treatment of Attention-Deficit/Hyperactivity Disorder Drug Duration of Effect FDA-approved for children 6 years old Methylphenidate C-II Short-acting IR formulations: Ritalin, Methylin, generics Intermediate-acting Ritalin SR Methylphenidate SR Metadate ER Methylin ER 3 5 3 8 Long-acting Metadate CD a 8 10 Initial Dose and Available Strengths 5 mg two or three times daily; available as: 5, 10, 20 mg tablets SR, ER doses; corresponds to the IR dose 20 mg every AM; available as: 10, 20, and 30 mg capsules Usual Dosing Range Maximum Dose 5 20 mg two or three times a day; max dose: 60 mg/day 20 40 mg every AM or 40 mg every AM and 20 mg in the early afternoon; max dose: 60 mg/day 20 40 mg every AM and 20 mg in early afternoon; max dose: 60 mg/day Ritalin LA b 20 mg every AM; available as: 20, 30, and 40 mg capsules Concerta c 12 18 mg every AM; available as 18, 27, 36, and 54 mg tablets; 90% bioavailability of IR Daytrana (transdermal system) 12 (when patch worn for 9 ) 10 mg (patch size 12.5 cm 2 ); apply each morning and remove after 9 d 20 60 mg/day, given every AM; max dose: 60 mg/day 27 54 mg in youths <12 years old; up to 72 mg/day in adolescents and adults, given every AM 10 30 mg (patch size 12.5 37.5 cm 2 ); drug active for 3 after patch removal Dexmethylphenidate C-II Short-acting Dexmethylphenidate (Focalin) FDA-approved for children 6 years old 3 5 Long-acting Focalin XR e 8 12 2.5 mg every AM or twice a day; available as 2.5, 5, and 10 mg tablets 5 mg every AM; available as 5, 10, 20 mg capsules 5 10 mg/day given twice a day; max initial dose: 7.5 mg/day; max dose: 20 mg/day 5 10 mg/day, given every AM; max dose: 30 mg/day
Amphetamine salts C-II FDA approved for children 3 years old Short-/Intermediateacting Mixed amphetamine generics, Adderall 4 6 2.5 mg every AM one or two times daily 10 40 mg/day (divided into two doses) FDA-approved for children 6 years old Dextroamphetamine C-II Generics, Dexedrine, Dextrostat 4 6 2.5 mg every AM to two or three times daily 5 15 mg twice a day; max dose: 40 mg/day Long-acting Mixed amphetamine salts, Adderall XR 10 12 5 to 10 mg every AM once daily Max dose: 30 mg/day Lisdexamfetamine f 10 14 Available as 20, 30, 40, 50, 70 mg Max dose: 70 mg/day 20 30 mg once daily every AM a Metadate CD contains 30% IR and 70% ER beads. b Ritalin LA contains 50% IR and 50% ER beads; uses the proprietary SODAS technology. c Concerta uses the proprietary OROS technology; ER inner compartments coated with an IR layer. d Daytrana patches are applied to clean, dry area on hip. e Focalin XR contains 50% IR and 50% ER beads. f Lisdexamfetamine is a prodrug of dextroamphetamine. Lisdexamfetamine has a longer onset than other amphetamine formulations but also a longer duration. ER = extended release; FDA = U.S. Food and Drug Administration; IR = immediate release; LA = long acting; OROS = osmotic-release oral system; SODAS = spheroidal oral drug absorption system; SR = sustained release; XR = extended release.
Table 2. Dosing of Nonstimulant Drugs for Attention-Deficit/Hyperactivity Disorder Drug Dosing Range and Titration Schedule Special Dosing Considerations Atomoxetine (Strattera) Bupropion (Wellbutrin, SR, XL) Not FDA-approved for ADHD 70 kg: start at 0.3 to 0.5 mg/kg every AM or twice a day; max dose: 1.4 mg/kg per day >70 kg: start at 40 mg every AM or 20 mg twice a day; max dose: 100 mg/day 50 300 mg/day; 3 mg/kg per day by end of week one; can increase to 6 mg/kg per day or max dose of 300 mg/day as tolerated Allow at least 2 weeks of a given dose before titrating upward; divided doses twice daily may be better tolerated Should not be used if seizure disorder or eating disorder is present α 2 -Adrenergic Agonists Clonidine (Catapres) Not FDA-approved Clonidine ER (Kapvay) Guanfacine (Tenex) Not FDA-approved Guanfacine ER (Intuniv) 0.05 mg two or four times daily; can increase as tolerated to 0.1 0.4 mg/day 0.1 mg twice daily; can increase to 0.2 mg twice a day; max dose: 0.4 mg/day 0.5 once to twice a day; can increase as tolerated to 1 4 mg/day 1 mg in the morning or evening, titrate as tolerated to response; do not give with high-fat meal Requires dosing three to four times daily; IR; may need higher dose if given with atomoxetine. FDA-approved for monotherapy or as an adjunct to stimulant therapy; can help with insomnia Not FDA-approved; need higher dose if administered with atomoxetine Effective dose higher in heavier children; increased dose needed with CYP3A4 inducers (e.g., carbamazepine, rifampin); decrease dose if given with CYP3A4 inhibitors (i.e., fluoxetine, sertraline); can help with insomnia CYP3A4 = cytochrome P450 3A4; ER = extended release; FDA = U.S. Food and Drug Administration; SR = sustained release; XL = extended release.