Let's Focus on ADHD

Dr. Hieber is a clinical pharmacist at Western Missouri Mental Health Center in Kansas City, Missouri. Dr. Purvis is a psychiatry pharmacy resident at Western Missouri Mental Health Center.

Though previously thought to be a childhood disorder, attention-deficit/hyperactivity disorder (ADHD) is now known to persist into adulthood.¹ "Growing out" of ADHD is unlikely; rather, one may learn to compensate for the impairment. Hyperactive symptoms may subside in adulthood, with inattentive symptoms becoming more prevalent. In both children and adults, ADHD can negatively affect socialization, school or occupational work, and relationships.

Affecting 8.7% of children and 4.4% of adults, ADHD is hereditary.^2,3 Several genes related to transmission of the neurotransmitter dopamine, and to a lesser extent, norepinephrine and serotonin, are implicated in ADHD.⁴ These neurotransmitters are associated with the brain's arousal network, which can be stimulated inappropriately in one who has ADHD. Other risk factors found in ADHD include prenatal exposure to tobacco or alcohol, low birth weight, and perinatal complications.⁵

Diagnosis

According to the Diagnostic and Statistical Manual of Mental Disorders, an individual with ADHD displays developmentally inappropriate levels of inattention, hyperactivity, and impulsivity persisting for at least 6 months.⁶ Presentation ranges from difficulty organizing tasks and forgetfulness in daily activities to excessive talking and interrupting others. Symptoms must begin in childhood, be present in 2 or more settings, and cause marked impairment in functioning. Despite this impairment, a number of effective treatment options exist for people with ADHD.

Treatment

Up to 80% of individuals with ADHD respond to stimulants; therefore, these agents are first-line options for both children and adults.^6,7 By enhancing the neurotransmission of dopamine and norepinephrine, stimulants have the greatest effect on social and classroom behaviors.⁸ The benefit of stimulants will often appear within days of achieving an adequate dose.

Evidence-based reviews conclude that all stimulant medications are equally effective, though an individual may respond to one stimulant over another.^7,9 Stimulants are available in short-acting, intermediate-acting, and long-acting formulations.¹⁰ Short-acting and intermediate-acting medications' peak effect occurs 1 to 3 hours after administration, necessitating the need for multiple daily dosing. School-age children may benefit from long-acting agents that eliminate the need for midday dosing. Depending on the formulation of the medication, ease of administration may be increased by crushing short-acting or intermediate-acting agents, or sprinkling the contents of a long-acting capsule over food.

Over the past decade, the advancement of new formulations has led to an increase in the use of long-acting agents. Examples include an osmotically controlled-release drug delivery system (methylphenidate HCl, Concerta), transdermal methylphenidate patch (methylphenidate transdermal system, Daytrana), and a conjugated d-amphetamine molecule (lisdexamfetamine dimesylate capsules, Vyvanse). Along with simplifying dosage regimens, these options were developed to decrease diversion and abuse of the medications.¹⁰

Guidelines suggest initiation with a low dose to minimize side effects and achieve the lowest effective dose.^6,11 Decreased appetite, sleep and gastrointestinal disturbances, irritability, headache, tachycardia, and jitteriness^8,12 are common, but often transient side effects. Although reported clinically, growth suppression was not reported consistently in clinical trials.¹³ Stimulants may cause a minimal increase in heart rate and blood pressure (dose-related); experts recommend that those treated with stimulants are monitored at baseline and periodically throughout treatment, especially children with underlying cardiac abnormalities or arrhythmias.^14,15 Whereas studies have not shown an association between stimulants and changes in electrocardiograms, monitoring is recommended in high-risk patients. Medications used to treat ADHD contain an FDA warning about the possible cardiovascular risks and psychiatric adverse events,¹⁶ along with a manufacturer's warning indicating the potential for abuse.

Atomoxetine (Strattera) is the only FDA-approved nonstimulant medication used as a major second-line, and in some cases first-line treatment for ADHD (those with a history or concern of substance abuse).^6,11,17,18 The drug is a selective norepinephrine reuptake inhibitor and has a slower onset of action than stimulants. It may take 2 to 4 weeks to determine clinical effectiveness. Side effects are similar to stimulants; however, an increase in sedation and sexual disturbances have been reported. Suicidal ideation and hepatotoxicity have been reported in the literature, and this risk is included in the manufacturer's warning label.¹⁹

Second-line treatment options should be considered for patients who have failed 2 to 3 stimulant medications. Along with atomoxetine, antidepressants (eg, venlafaxine, bupropion, tricyclic antidepressants) are second- or third-line agents.^17,20-22 These have shown only modest efficacy for the treatment of ADHD, but may be beneficial for patients with comorbid depression or substance abuse.

Several studies have indicated that modafinil, approved for treating narcolepsy, has shown improvement in ADHD.²³ Concerns of Stevens-Johnson syndrome led an FDA advisory committee to recommend against approval of modafinil for the treatment of ADHD in children. Clonidine and guanfacine, a₂-adrenergic agonists, may be adjunctive treatment options in children with ADHD, especially those experiencing sleep disturbances.^24-26

Behavioral interventions were not more effective than medication, according to recent evidence.²⁷ Pharmacists can play a major role in educating patients and caregivers.

References

1. Heath CT Jr, Wright HH, Batey SR. Attention deficit hyperactivity disorder: does it affect adults too? Southern Med J. 1990;83(12):1396-1401.

2. Froehlich TE, Lanphear BP, Epstein JN, Barbaresi WJ, Katusic SK, Kahn, RS. Prevalence, recognition, and treatment of attention deficit/hyperactivity disorder in a national sample of US children. Arch of Pediatr Adolesc Med. 161(9):857-864.

3. Kessler RC, Adler L, Barkley R, et al. The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am J Psychiatry. 163(4):716-723.

4. Faraone SV, Khan SA. Candidate gene studies of attention-deficit/hyperactivity disorder. J Clin Psychiatry. 67 (suppl 8):13-20.

5. Banerjee TD, Middleton F, Faraone SV. Environmental risk factors for attention-deficit hyperactivity disorder. Acta Paediatr. 96(9):1269-1274.

6. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000.

7. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. The MTA Cooperative Group. Multimodal Treatment Study of Children with ADHD. Arch Gen Psychiatry. 1999;56 (12):1073-1086.

8. McMaster University Evidence-Based Practice Center. Treatment of Attention-Deficit Hyperactivity Disorder. Ottawa, Canada: Canadian Coordinating Office for Health Technology Assessment; 1998.

9. Brown RT, Amler RW, Freeman WS, et al. Treatment of attention-deficit/hyperactivity disorder: overview of the evidence. Pediatrics. 2005;115(6):749-755.

10. Findling RL. Evolution of the treatment of attention-deficit/hyperactivity disorder in children: a review. Clin Ther. 2008;30(5):942-957.

11. Rappley MD. Attention deficit-hyperactivity disorder. N Engl J Med. 2005;(2)352:165-173.

12. Greenhill LL, Pliszka S, Dulcan MK, et al. Practice parameters for the use of stimulant medications in the treatment of children, adolescents, and adults. J Am Acad Child Adolesc Psychiatry. 2002;41(suppl 2):26S-49S.

13. Spencer T, Biederman J, Wilens T. Growth deficits in children with attention deficit hyperactivity disorder. Pediatrics. 1998;102(2 Pt 3):501-506.

14. Wilens TE, Hammerness PG, Biederman J, et al. Blood pressure changes associated with medication treatment of adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2005;66(2):253-259.

15. Vetter VL, Elia J, Erickson C, et al. Cardiovascular monitoring of children and adolescents with heart disease receiving medications for attention deficit/hyperactivity disorder: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young Congenital Cardiac Defects Committee and the Council on Cardiovascular Nursing. Circulation. 2008;117(18):2407-2423.

16. FDA Directs ADHD Drug Manufacturers to Notify Patients about Cardiovascular Adverse Events and Psychiatric Adverse Events. Food and Drug Administration Web site. www.fda.gov/bbs/topics/NEWS/2007/NEW01568.html. Accessed December 12, 2008.

17. Asherson P. Clinical assessment and treatment of attention deficit hyperactivity disorder in adults. Expert Rev Neurother. 2005;5(4):525-539.

18. Newcorn JH, Kratochvil CJ, Allen AJ, et al. Atomoxetine and osmotically released methylphenidate for the treatment of attention deficit hyperactivity disorder: acute comparison and differential response. Am J Psychiatry. 2008;165(6):721-730.

19. Abboud L. Lilly warns doctors about Strattera. Wall Street Journal. December 20, 2004:B4.

20. Edmund H. A comparative analysis of antidepressants and stimulants for the treatment of adults with attention-deficit hyperactivity disorder. J Fam Pract. 1999:28(1);15-20.

21. Wilens TE, Spencer TJ, Biederman J. A review of the pharmacotherapy of adults with attention-deficity/hyperactivity disorder. J Atten Disorder. 2002:5(40;189-202.

22. Conners CK, Casat CD, Gualtieri TC, et al. Bupropion hydrochloride in attention deficit disorder with hyperactivity. J Am Acad Child Adolesc Psychiatry. 1996;35(10):1314-1321.

23. Kumar, R. Approved and investigational uses of modafinil: an evidence-based review. Drugs. 2008: 68(13):1803-1839.

24. Conner DF, Fletcher KE, Swanson JM. A meta-analysis of clonidine for symptoms of attention deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 1999:38(12);1551-1559.

25. Scahill L, Chappell PB, Kim YS, et al. A placebo-controlled study of guanfacine in the treatment of children with tic disorders and attention deficit hyperactivity disorder. Am J Psychiatry. 2001;158(7):1067-1074.

26. Wolraich ML, Wibbelsman CJ, Brown, TE, et al. Attention-deficit/hyperactivity disorder among adolescents: a review of the diagnosis, treatment, and clinical implications. Pediatrics. 2005:115(6);1734-1746.

27. American Academy of Pediatrics. Subcommittee on Attention-Deficit/Hyperactivity Disorder and Committee on Quality Improvement. Clinical practice guideline: treatment of the school-aged child with attention-deficit/hyperactivity disorder. Pediatrics. 2001;108(4);1033-1044.

28. Challman TD, Lipsky JJ. Methylphenidate: its pharmacology and use. Mayo Clin Proc. 2000;75(7):711-21.

29. Adderall [package insert]. Princeton, NJ: Sandoz Inc;2007. Accessed April 30, 2009.

30. Daytrana [package insert]. Wayne, PA: Shire Pharmaceuticals;2008. Accessed April 30, 2009.

31. Vyvanse [package insert]. Wayne, PA: Shire Pharmaceuticals; 2007. Accessed April 30, 2009.

32. Concerta [package insert]. Mountain View, CA: ALZA Corp;2007. Accessed April 30, 2009.

33. Focalin [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2007. Accessed April 30, 2009.

34. Methylphenidate extended-release [package insert]. Corona, CA: Watson Laboratories;2007. Accessed April 30, 2009.