Editorial

Larry Greenhill, MD, Ruane Professor of Clinical Psychiatry and Director of the Research Unit in Pediatric Psychopharmacology, New York State Psychiatric Institute, New York, New York

Attention-deficit/hyperactivity disorder (ADHD), whose core symptoms include inattention, hyperactivity, and impulsivity,^1,2 is one of the major public health problems in the United States (U.S.), accounting for significant morbidity and disability in children and adolescents. Children with ADHD often have academic difficulties in the form of inability to sustain attention, and they may also manifest other behavioral problems, such as disruptive behavior in class, opposing or defying parents and teachers. As children with ADHD enter adolescence and adulthood, they are at higher risk for a number of other problems, such as substance abuse, driving accidents, and/or difficulties with employment or interpersonal relationships. Methylphenidate has long been the mainstay of ADHD treatment, but the requirement for multiple daily doses with immediate-release methylphenidate is socially stigmatizing and inconvenient for patients (during school) which raises the potential for nonadherence.

In August 2000, the oral osmotic (OROS) delivery system of methylphenidate (Concerta) was approved by the Food and Drug Administration (FDA) for the treatment of ADHD. OROS methylphenidate significantly improves the core symptoms of ADHD and is dosed once daily. Moreover, its osmotically released drug-delivery technology reduces the opportunity for drug diversion and misappropriation of the active ingredient since the extended-release tablet cannot be pulverized. At the recently held 49th Annual Meeting of the American Academy of Child & Adolescent Psychiatry in San Francisco, California, the results of one of the largest controlled clinical trials in adolescent patients with ADHD were presented. This randomized, double-blind, placebo-controlled clinical trial evaluated the safety and efficacy of 18 mg, 36 mg, 54 mg, and 72 mg OROS methylphenidate.³ OROS methylphenidate significantly improved all ADHD parameters studied, including physician-rated scales of ADHD symptom severity (eg, ADHD rating scale and Clinician's Global Impression (CGI) evaluations); parent-rated scales, including a measure of parent-child conflict; and self-ratings of symptom severity by the adolescents.

This is an important trial for several reasons. First, adolescent patients are often excluded from clinical trials evaluating ADHD medications, and it has not been well established whether they require the same doses that have been used successfully in young children. Secondly, many clinicians report using higher doses of OROS methylphenidate (>54 mg) in their adolescent patients. In fact, the American Academy of Pediatrics suggests dosing OROS methylphenidate from 18 to 72 mg daily for ADHD.⁴

Although many clinicians believe that ADHD is primarily a disorder of early childhood, recent evidence suggests that residual symptoms persist well into adolescence and adulthood in a majority of patients. At the same meeting, Faraone and colleagues reported the results of a statistical analysis⁵ that challenges the premise of the age-dependent decline of ADHD first proposed in 1996 by Hill and Schoener.⁶ The analysis revealed a greater incidence of ADHD persisting into adolescence and adulthood depending, in part, on what definition of persistence is used.

This year's meeting offered promising data on the pharmacologic treatment of ADHD. In addition to new oral methylphenidate formulations, there were studies presented on transdermal methylphenidate and phase 3 trial data on atomoxetine.

Attention-Deficit/Hyperactivity Disorder: Beyond Childhood

New data presented at the 49th Annual Meeting of the American Academy of Child & Adolescent Psychiatry indicate that many cases of childhood onset attention-deficit/hyperactivity disorder (ADHD) persist into adolescence and adulthood. These new findings challenge the long-held concept of age-dependent decline of ADHD proposed by Hill and Schoener.⁶ First proposed in 1996, Hill and Schoener created a mathematical model that predicted an exponential decline in the rate of ADHD to 0.8% at age 20 and 0.05% ay age 40, suggesting that the incidence of ADHD in adolescents and adults is rare.

"But, Hill and Schoener studied persistence rates using full Diagnostic and Statistical Manual of Mental Disorders (DSM)-III-R Criteria for ADHD, and this definition of remission may not be ideal," explained Stephen V. Faraone, PhD, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.⁵ "And the presence of residual impairing symptoms is a clinical concern," he continued. "Our analysis of ADHD outcome studies included both syndromatic and symptomatic persistence".

Using a sophisticated exponential model, the analysis revealed that only 0.9% of adults who had had ADHD as children would continue to meet the full threshold diagnoses of DSM (II, III, III-R or IV) criteria as adults but 39% would show evidence of impairing symptoms. These findings support recent follow-up studies that suggest that up to 60% [percentage varies depending on diagnostic criteria used] of children with ADHD will have symptoms persisting into adulthood.^7,8

Continuing Comorbidity

As in children, there is significant comorbidity in adults with ADHD. High rates of anxiety disorders (50%), substance abuse (27%-47%), and antisocial personality disorders (12%-27%) have been reported by Spencer et al.⁷ Conversely, approximately 40% of adults with ADHD will not have coexisting anxiety, affective or personality disorder but still have significant impairment (eg, concentration, memory).⁷

Methylphenidate and Adolescent Patients

There are no pharmacologic treatments specifically indicated for the treatment of adolescent and adult ADHD. In fact, the vast majority of research on ADHD treatment has involved children, with methylphenidate representing the standard of ADHD treatment. Pharmacologic treatments that have been used for ADHD include dextroamphetamine (Dexedrine), dextroamphetamine/amphetamine salts (Adderall), methamphetamine (Desoxyn), desipramine (Norpramin), bupropion (Wellbutrin) and other extended-release formulations of methylphenidate (Metadate CD, Ritalin-LA). Adjunctive nonpharmacologic therapies may be used to complement pharmacologic treatment and include individual and family therapy, behavior modification, cognitive therapy, parent support groups, and school involvement.

The efficacy of immediate-release methylphenidate in the treatment of ADHD has been well established.⁹ However, the duration of effect for immediate-release methylphenidate is approximately 3 to 6 hours.^10-12 In August 2000, the FDA approved OROS methylphenidate which managed ADHD symptoms with only one morning dose for a period of 12 hours.¹³ Although its use in adolescent and adult patients is less well studied, the American Academy of Child & Adolescent Psychiatry suggests that OROS methylphenidate may be well-suited for adolescent patients on the basis of adherence and resistance to diversion.¹⁴

Efficacy and Safety of OROS Methylphenidate in Adolescents with ADHD

Larry L. Greenhill, MD, on behalf of The Adolescent Study Group, New York State Psychiatric Institute, New York, New York

Larry L. Greenhill, MD, of the New York State Psychiatric Institute, New York, New York reported the results of a double-blind, placebo-controlled study designed to evaluate the efficacy and safety of OROS methylphenidate in 177 adolescent patients, ages 13 to 18 years old with confirmed diagnosis of ADHD.³ Following a one-week washout period, patients were titrated to an individualized dose of OROS methylphenidate of 18 mg, 36 mg, 54 mg, or 72 mg and then randomized to their respective dose or placebo for a 2-week period. Patients were then eligible to receive OROS methylphenidate for an on-going 8-week open-label follow-up phase. The primary efficacy measure was the ADHD Rating Scale. Secondary measures included the Conners-Wells' Self-Report Scale (CASS-L), Child Conflict Index (CCI), and the Clinical Global Impression (CGI) scale.

Of the patients randomized to the double-blind phase of the study, 65 (36.7%) patients were individualized to the 72 mg dose, 50 (28.2%) patients to the 54 mg dose, and 49 (27.7%) and 13 (7.3%) to the 36 mg and 18 mg doses, respectively.

OROS methylphenidate was significantly superior to placebo (P = .0010) on the investigator rated ADHD Rating Scale (Figure 1). Parents and caregivers reported similar results.

Adolescent patients, using the Conners-Wells' Self-Report Scale, rated ADHD symptoms significant lower (P = .0011) on OROS methylphenidate than on placebo. Adolescent-parent conflict (as measured by CCI) was significantly improved (P = .0051) on OROS methylphenidate. (Figure 2).

Treatment with OROS methylphenidate was generally well tolerated. The only study-drug related adverse event with an incidence >5% was headache (placebo 7.8%, OROS methylphenidate 6.9%).

These findings demonstrate that once-daily treatment with OROS methylphenidate produces statistically and clinically significant improvements in the core symptoms of ADHD in adolescent patients.

Agents in Development

The results of a phase III trial demonstrated that once-daily treatment with a transdermal methylphenidate formulation significantly improved a number of ADHD rating scales in children 6 to 12 years old.¹⁵ The transdermal application of methylphenidate could preclude potential compliance problems. Another potential treatment for ADHD under clinical investigation is atomoxetine. In a double-blind, placebo-controlled trial of atomoxetine in children between the ages of 6 and 16 years, once-daily treatment with atomoxetine produced significantly greater improvement than placebo in the study's primary endpoint (the decrease from baseline in the ADHD rating scale) and also improved secondary outcome measures such as rating subscale scores for hyperactivity/impulsivity and inattention.¹⁶ Adverse events more common with atomoxetine as compared to placebo included (respectively) decreased appetite (16.5% vs 5.8%), vomiting (15.3% vs 6.8%), and dyspnea (8.2% vs 1.4%).

Conclusion

Attention-deficit/hyperactivity disorder, whose core symptoms include inattention, hyperactivity, and impulsivity, is one of the major behavioral problems in the United States, accounting for significant morbidity in children and adolescents with considerable impact on the patient's and family's quality of life. Although recent research suggests that many patients continue to exhibit residual symptoms of ADHD throughout adolescence into adulthood, the management of ADHD in adolescents and adults is not as well researched at present. The results of the first multisite, double-blind, placebo-controlled clinical trial in adolescent patients comparing OROS methylphenidate to placebo under double-blind conditions described significant improvements in core ADHD symptoms as rated by adolescents, their parents, and physicians. However, the results of this study suggest that adolescent patients may require higher doses of OROS methylphenidate than are currently used in younger children. Once-daily treatment with OROS methylphenidate was well tolerated by patients and should assist in patient adherence.

References

1. Reiff MI, Banez GA, Culbert TP. Children who have attentional disorders: diagnosis and evaluation. Pediatr Rev. 1993;14:455-465.
2. Barkley RA. Attention Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment. 2nd ed. New York, NY: Guilford Press; 1996.
3. Greenhill LL, on behalf of the Adolescent Study Group. Efficacy and safety of OROS(r) MPH in adolescents with ADHD. Presented at the 49th Annual Meeting of the American Academy of Child & Adolescent Psychiatry, October 22-27, 2002, San Francisco, California. Poster Presentation 4.
4. Clinical practice guideline: treatment of the school-aged child with attention-deficit/hyperactivity disorder. American Academy of Pediatrics Subcommittee on Attention-Deficit/Hyperactivity Disorder Committee on Quality Improvement. Pediatrics. 2001;108:1033-1044.
5. Faraone S. A re-evaluation of the age-dependent decline of attention deficit/hyperactivity disorder. Presented in the Symposium "New Research in Adult ADHD" during the 49th Annual Meeting of the American Academy of Child & Adolescent Psychiatry, October 23, 2002, San Francisco, California.
6. Hill JC, Schoener EP. Age-dependent decline of attention deficit hyperactivity disorder. Am J Psychiatry. 1996;153:1143-1146.
7. Spencer T, Biederman J, Wilens T, et al. Adults with attention-deficit/hyperactivity disorder: a controversial diagnosis. J Clin Psychiatry. 1998;59(suppl 7):59-68.
8. Spencer T, Biederman J, Wilens T, et al. Is attention deficit hyperactivity disorder in adults a valid disorder? Harvard Rev Psychiatry. 1994;1:326-335.
9. Goldman LS, Genel M, Bezman RJ, et al. Diagnosis and treatment of attention-deficit/hyperactivity disorder in children and adolescents. JAMA. 1998;279: 1100-1107.
10. Methylphenidate. In: Burnham TH, ed. Drug Facts and Comparisons. 2002. St. Louis: Facts and Comparisons, Inc., 773-774a.
11. Shader RI, Harmatz JS, Oesterheld JR, et al. Population pharmacokinetics of methylphenidate in children with attention-deficit hyperactivity disorder. J Clin Pharmacol. 1999;39:775-785.
12. Ritalin Prescribing Information [package insert]. Novartis Pharmaceuticals. Available at http://www.pharma.us.novartis.com. Accessed November 1, 2002.
13. Concerta Prescribing Information [package insert]. McNeil Consumer and Specialty Pharmaceuticals. Available at http://www.concerta.net. Accessed November 1, 2002.
14. Practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults. J Am Acad Child Adolesc Psychiatry. 2002;41(2 suppl):26S-49S.
15. Greenhill LL, Pelham WE Jr, Lopez FA, et al. Once-daily transdermal methylphenidate improves teacher, parent, and CGI-I ratings. Presented at the 49th Annual Meeting of the American Academy of Child & Adolescent Psychiatry. October 22-27, 2002, San Francisco, California.
16. Michelson D, Allen AJ, Kelsey D, et al. Once-daily atomoxetine treatment for children and adolescents with ADHD. Presented at the 49th Annual Meeting of the American Academy of Child & Adolescent Psychiatry. October 22-27, 2002, San Francisco, California.

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Disclosure
Larry Greenhill, MD
Grant/Research Support-NIMH, Shire, McNeil Consumer and Specialty Pharmaceuticals; Consultant-Shire, Novartis, Celltech, Lilly, Noven Pharmaceuticals, Inc., McNeil Consumer and Specialty Pharmaceuticals; Speakers Bureau-McNeil Consumer and Specialty Pharmaceuticals

This report contains information on commercial products that are unlabeled for use or investigational uses of products not yet approved. Concerta, Adderall and Desoxyn are only indicated for ADHD ages 6 to 12 years. Dexedrine is indicated for ADHD ages 3 to 16 years. Norpramin and Wellbutrin are not indicated for ADHD.

This report is supported by an educational grant from McNeil Consumer and Specialty Pharmaceuticals.

The opinions expressed in this publication are those of the participating faculty and do not necessarily reflect the opinions or the recommendations of their affiliated institutions: University of Medicine & Dentistry of New Jersey; MMC, Inc.; or any other persons. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients' conditions, assessment of possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with the recommendation of other authorities. This Attention-Deficit/Hyperactivity Disorder Express Report™ includes discussion of treatment and indications outside of current approved labeling. This Attention-Deficit/Hyperactivity Disorder Express Report™ was made possible through an educational grant from McNeil Consumer and Specialty Pharmaceuticals.

© 2002 Millennium Medical Communications, Inc. and UMDNJ-Center for Continuing and Outreach Education