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Pharmacology of Adult ADHD with Stimulants


Thomas J. Spencer, MD


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CNS Spectr. 2007;12:4(Suppl 6):8-11

An expert panel review of clinical challenges in psychiatry

This supplement is supported by an educational grant from Shire Pharmaceuticals Inc.

Accreditation Statement

This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians. 

Credit Designation

The Mount Sinai School of Medicine designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Faculty Disclosure Policy Statement

It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer reviewed and approved by Eric Hollander, MD, Chair and Professor of Psychiatry at The Mount Sinai School of Medicine. Review Date: April 10, 2007.

Statement of Need and Purpose

Up to 65% of children with attention-deficit/hyperactivity disorder (ADHD) continue to display behavioral problems and symptoms of the disorder into their adult lives. ADHD appears to have a deleterious impact upon the daily functioning of the majority of adults, negatively affecting their educational, social, and occupational lives and interfering with their ability to establish and maintain close relationships. Differing patterns of comorbidity and symptom heterogeneity in adults pose new conceptual, diagnostic, and treatment challenges. Most adults with ADHD have not been properly diagnosed or treated. Diagnosis requires careful consideration of other psychiatric and medical disorders that may mimic symptoms of the disorder. Under the best circumstances, effective treatment is multi-modal. Stimulants and noradrenergic and dopaminergic antidepressants have been shown to be useful medical interventions for adult ADHD. More research is needed on the efficacy of treatment for comorbid ADHD, use of combined medications, and the combination or medication and psychosocial treatment.

Target Audience

This activity is designed to meet the educational needs of psychiatrists.

Goal of the Activity

• To educate physicians on the latest diagnostic strategies and therapeutic options for adults with ADHD as well as the neurobiology behind this disorder.

Learning Objectives

• Review the prevalence, clinical presentation, and diagnostic methods of adult ADHD.
• Evaluate recent genetic and biologic evidence for ADHD and its impact on diagnosis and treatment.
• Assess the latest treatments available, including mechanism of action of ADHD medications and effect of comorbidities, to provide an overview of recommended management.

Acknowledgment of Commercial Support

This activity has been made possible in part by an educational grant from Shire.

Peer Reviewers

Eric Hollander, MD, reports no financial, academic, or other support that may pose a conflict of interest.

David L. Ginsberg, MD, is an independent contractor for AstraZeneca and GlaxoSmithKline; and receives research support from Cyberonics.

To Receive Credit for this Activity

Read this supplement, reflect on the information presented, and complete the CME quiz and evaluation on pages 15 and 16. To obtain credit, you should score 70% or better. Early submission of this posttest is encouraged to measure outcomes for this CME activity. Please submit this posttest by April 1, 2009 to be eligible for credit.

Release date: April 1, 2007

Termination date: April 30, 2009

The estimated time to complete this activity is 1 hour.

Faculty Affiliation and Disclosure

Dr. Spencer is associate chief in the Clinical and Research Program in Pediatric Psychopharmacology at Massachusetts General Hospital, and associate professor of psychiatry at Harvard Medical School in Boston.


Disclosures: Dr. Spencer is on the speaker’s bureaus of Eli Lilly, GlaxoSmithKline, McNeil, Novartis, and Shire; is on the advisory boards of Eli Lilly, GlaxoSmithKline, McNeil, Novartis, and Shire; and receives research support from Eli Lilly, GlaxoSmithKline, McNeil, the National Institute of Mental Health, Novartis, and Shire.

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a lifelong condition that begins in childhood and continues with adult manifestations related to the core symptoms. Approximately 50% to 75% of children with ADHD continue to meet criteria for the disorder as adolescents and adults. Adults with the disorder increasingly present to primary care physicians, psychiatrists, and other practitioners for diagnosis and treatment. Understanding the diagnosis of ADHD in adults requires knowledge of age-dependent decline of symptoms over time. Retrospective recall of symptoms and impairment are valid methods of diagnosing the disorder. ADHD is also a brain disorder with a strong neurobiologic basis, complex etiology, and genetic component. Genetic and environmental vulnerabilities give rise to abnormalities in the brain and subsequent behavioral and cognitive deficits, which may produce the symptoms associated with ADHD. Magnetic resonance imaging studies of ADHD have provided evidence that abnormalities in the brain are caused by the disorder itself rather than treatment of the disorder. Psychiatric comorbidity is common among patients with ADHD and tends to complicate treatment. Acute and long-term use of long-acting stimulant formulations (methylphenidate and amphetamine compounds) have shown robust efficacy and tolerability consistent with the treatment response established in children with ADHD. Non-stimulant medications have demonstrated efficacy as well, and may be preferred in patients with tic and substance use disorders. 

In this expert roundtable supplement, Timothy E. Wilens, MD, reviews the epidemiology and clinical presentation of adult ADHD. Next, Joseph Biederman, MD, provides an overview of recent advances in the neurobiology of ADHD. Thomas J. Spencer, MD, reviews stimulant treatment of adult ADHD, and Lenard A. Adler concludes with a discussion of non-stimulant trials in adult ADHD.

Introduction

Until recently, treatment studies of adult attention-deficit/hyperactivity disorder (ADHD) have not been as sophisticated as existing studies of children and adolescents due to confusion and controversy about the syndromatic boundaries of adult ADHD. Much of the controversy was related to the interpreting the transformation of ADHD symptoms with age, where the overt symptoms of hyperactivity decrease and those of attention and other executive issues become more prominent. Contributing to this issue has been a relative lack of standardized assessment methods for determining ADHD in adults. The early studies of adults with ADHD with stimulants primarily focused on short-acting or immediate-release (IR) methylphenidate.

Early studies demonstrated a limited response of adult ADHD to stimulants, clearly not as profound as those observed in children and adolescents. A number of issues were thought to contribute to these differences. The diagnostic criteria was not well operationalized. The rating instruments tended to be over-inclusive, including symptoms that could be more specific to other disorders or non specific impairments. Finally, the early studies used lower (weight-corrected) doses than those used in the pediatric studies. Investigators thought that adults would respond adequately to lower doses, or were concerned that adults would have more side effects or euphoria on higher doses.

Short-Acting Methylphenidate Compounds

Our group conducted the first study to systematically examine higher doses of methylphenidate in the mid 1990s.1 Consistent with pediatric studies, methylphenidate IR was dosed 3 times per day to a target dose of 1 mg/kg/day. In this pilot study, careful attention to diagnosis and comorbidities, more robust dosing and a specific ADHD rating scale (the ADHD Rating Scale (ADHD-RS) lead to a higher response, consistent with those reported in pediatric studies.

In a replication of that study,2 we examined a much larger sample of adults with ADHD who were randomized to placebo or methylphenidate IR TID up to 1.3 mg/kg/day. There was a low placebo response and a substantial drug response with increasing dose over the 6 weeks of the study (Slide 1). Doses were optimized individually as they would be in clinical practice. While most subjects generally tolerated 1 mg/kg/day, individuals were on slightly different doses depending on their individual response and tolerability.

In a 6-month continuation phase of the study,3 patients who responded in the first 6 weeks maintained their response fully for 6 months, demonstrating that the robust response was not transient. Global Assessment of Functioning scores also increased rapidly by 6 weeks and the high level of improvement was maintained over the full 6 months.

Long-Acting Methylphenidate Compounds

Similar to the trends in treatment of children and adolescents with ADHD, there has been a shift to new longer-acting medications in adults with ADHD. These medications are formulations of short-acting medications that allow effective treatment throughout the day with once-a-day dosing.

OROS Methylphenidate

The first long-acting methylphenidate compound to be developed and approved was an oral osmotic release system (OROS) formulation. This formulation consists of an outer layer of IR methylphenidate and an inner compartment with slow release designed for 12 full hours of treatment.

Biederman and colleagues4 utilized the same methodology of the methylphenidate IR study mentioned above, but instead of three doses of methylphenidate IR, comparable doses of OROS methylphenidate were given once per day. A new generation of a specific and sensitive rating scale for adult ADHD was used called the Adult ADHD Investigator Symptom Rating Scale (AISRS). Results on the AISRS revealed a robust response over the 6 weeks, that was equivalent to that of methylphenidate IR given TID (Slide 2).

In both this study and the methylphenidate IR studies, there was a careful review of tolerability, safety, and cardiovascular issues given the relatively higher doses. Symptoms that commonly occur with stimulants, such as insomnia, appetite suppression, dry mouth, or agitation, were generally mild and consistent with studies in children. Appetite suppression was less of a concern in adults than in children and adult subjects tended to be slightly overweight. Weight loss was mild and limited despite the full, all-day dosing.

Similar to what had been observed in other studies, there were small, statistically significant increases in systolic and diastolic blood pressure, and heart rate that were not generally clinically significant. A key difference between adults and in children is that adults tend to gradually escalate blood pressure with age, thus a subset of adults who present for treatment for adult ADHD will have asymptomatic borderline hypertension prior to treatment. Therefore, blood pressure needs to be assessed at the beginning of treatment. Even though low-grade hypertension is not specific to ADHD and occurs in rates equal to that of the normal population, one has to be more careful when prescribing a drug that will raise blood pressure and pulse even if only slightly.

There was no change in electrocardiogram (ECG) parameters between placebo and drug in the OROS study even with full dosing. However, due to the concern about cardiovascular issues in adults, it is recommended that clinicians take a history of any previous cardiac issues, as well as exercise tolerability including symptoms of syncope, dyspnea, palpitations, and chest pain. A clinical history of the cardiovascular system is the most sensitive screening approach to determine the safety of appropriate candidates for treatment.  

Dextro-methylphenidate Extended Release

Dextro-methylphenidate extended release (d-methylphenidate XR), is the only methylphenidate compound currently Food and Drug Administration-approved for adults. D-methylphenidate is a stereoisomer that is contained in a beaded capsule providing bi-modal release (immediate and delayed). The formulation is designed for 12 hours of treatment. It uses spheroidal oral drug absorption system (SODAS) technology, which consists of a capsule containing of spherical beads 1–2 mm in diameter. Each capsule contains 50% IR beads and 50% XR polymer-coated beads. The beads are coated with soluble polymers designed to dissolve. Fluid enters the core of these beads and dissolves active methylphenidate. Approximately 4 hours after administration, a second dose of methylphenidate is released.

In a dose-finding study by Spencer and colleagues,5 d-methylphenidate XR was administered to adults with ADHD on an a priori randomized dosing basis, rather than individually optimized. Regardless of individual characteristics, one fourth of the study participants were randomized to placebo, one fourth to a dose of 20 mg, one fourth to a dose of 30 mg, and one fourth to a dose of 40 mg. All of the doses were effective as demonstrated by improved ADHD-RS scores. There was a modest dose-response difference in percentage of subjects with >30% improvement of symptoms. While, at this point, only the lowest dose, 20 mg, is FDA approved, in our clinical practice, we have found that some individuals require higher doses (>20 mg) that are not yet approved by the FDA.

In a follow-up study by Adler and colleagues,6 d-methylphenidate XR demonstrated long-term symptom control as shown by ADHD-RS scores (Slide 3). There was a change in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition ADHD-RS total score at the end of each treatment phase. After the acute phase, d-methylphenidate XR was individually optimized in an open-label fashion at mean daily doses of between 10 and 40 mg, for up to 6 months. At the end of the 5-week double-blind study, patients treated with d-methylphenidate-XR had greater reduction in mean ADHD-RS total scores compared to patients receiving placebo (-17.5 versus -12.2). During the 6-month extension phase, patients previously administered placebo had a greater reduction in mean ADHD-RS total scores compared to patients previously treated with d-methylphenidate XR (-10.2 versus -8.4).

Vital signs were evaluated for the controlled portion of the d-methylphenidate XR study. Of the vital signs only the increase in pulse was statistically significant. Spencer and colleagues5 reported that mean changes from baseline in systolic and diastolic blood pressure were minimal and not statistically significant. A heart rate increase of 3.1 bpm was observed in patients in the d-methylphenidate XR 20 mg treatment group compared to a slight decrease of -1.4 bpm for placebo (Slide 4). No subjects who received d-methylphenidate XR experienced a clinically significant change in a cardiovascular measurement. In the placebo group, two patients experienced clinically notable low blood pressure values. No clinically relevant ECG abnormalities were observed, and other, minor ECG abnormalities were not associated with cardiovascular symptoms. Somewhat greater weight loss was observed in patients in the d-methylphenidate XR treatment groups: -1.4 kg versus -0.1 for placebo and was not of general concern. Clinically notable weight loss was observed in six patients treated with d-methylphenidate XR and one patient treated with placebo.  

 

Amphetamine Compounds   

Amphetamines are the other type of stimulants used in ADHD treatment. Until recently there were no controlled studies of amphetamines for adult ADHD. We conducted a pilot study of mixed amphetamine salts (MAS) IR using twice-a-day dosing because MAS has an approximate 6 hour duration.7 Using the same methodology as the methylphenidate study described above, a robust effect and good tolerability were observed.   

Mixed Amphetamine Salts Extended Release

A long-acting form of mixed amphetamine salts (MAS XR) is available as well, and involves a pulse delivery system with beads in a capsule. This capsule formulation contains equal proportions of IR and XR beads and the active ingredient is identical to the IR formulation. The IR beads are designed to follow a time course similar to the IR formulation, and the XR beads are designed to release the drug approximately 4 hours post-dose. Thus, a single 20-mg MAS XR dose is designed to follow a time course similar to two 10 mg IR tablets given approximately 4 hours apart. MAS XR is designed to last 12 hours. MAS XR is the other stimulant and only amphetamine product that is currently FDA approved for the treatment of adults.

Weisler and colleagues8 conducted a large study of adults with ADHD evaluating both acute and long-term results of MAS XR (Slide 5). In the short-term, dose-finding study, subjects were assigned 20 mg, 40 mg, or 60 mg doses a priori. Dosing was increased over 3 weeks and held constant the last week. The response of subjects on each dose was significantly improved over placebo and there was a modest dose response with increasing dose. The drug was effective and well-tolerated, with the same side-effect profile as described for the methylphenidate compounds.

Currently only the 20 mg dose of Adderall XR is FDA approved in adults. However, in a post-hoc analysis a larger dose-response was found for patients with more severe ADHD (baseline ADHD-RS score ≥32). The 20-mg dose was effective compared with placebo in general, but its benefits were mostly limited to those patients whose symptoms were less severe. However, for patients whose symptoms were more severe, doses of MAS XR up to 60 mg/day showed significant improvement and suggest that there is a linear dose-response trend.

In a long-term follow-up extension study subjects had doses individually optimized.9 Dose adjustments in 20-mg increments were allowed at any clinic visit, and were based on the clinical investigator’s judgment of optimal treatment, as assessed by effectiveness (ADHD-RS scores at each visit) and tolerability (adverse events and other safety measures). Patients experienced ADHD-RS total score improvement of 49% by week 4 in the short-term controlled study, and continued improvement was demonstrated in the long-term study following individual dose optimization that occurred during the first 1–2 months of the long-term study. At month 2 of the long-term study, mean ADHD-RS total scores were statistically significantly lower (P<.05) than at the beginning of the long-term study, demonstrating that patients experienced additional significant symptom improvement during the first 2 months of the long-term study. The difference between mean week 4 ADHD-RS scores and mean month 2 ADHD-RS scores represents a 31% reduction in symptoms from the start of the long-term study to the 2-month time point.

Importantly, the open-label part of this study lasted for 2 years. As with methylphenidate, those who improved in the first few weeks remained improved for the full duration of the long-term study. Despite full and effective all-day treatment, there were low rates of adverse effects, and small, statistically significant  cardiovascular changes that were not clinically significant and which remained fairly stable over the 2 years.

Further Directions

Other compounds on the horizon that have not yet been approved for use in adult ADHD include an amphetamine pro-drug (Vyvanse), a methylphenidate patch (Daytrana), and SPD 465. Vyvanse is an amphetamine pro-drug that has unusual safety characteristics, and has the same efficacy profile and 12 hour duration as MAS XR. Daytrana is a transdermal delivery system (patch) methylphenidate compound that has been approved for children and adolescents and provides 12 hours of treatment. The patch is worn for 9 hours and the medication lasts for 3 hours after removal. While it has not been studied or approved in adults, it has some potential for use in that population. Finally, a 16-hour, extended-release amphetamine (MAS) formulation, SPD 465, is being developed. This formulation is composed of three bead compartments—immediate, intermediate, and long-acting delivery for longer treatment.

Conclusion

Acute and long-term use of long-acting stimulant formulations have been studied in adults. When employing the proper dosing, diagnostic criteria and rating scale instrumentation, a robust efficacy and tolerability of stimulant treatment in adults has been documented that is consistent with the treatment response established in children with ADHD.

References

1. Spencer T, Wilens T, Biederman J, Faraone S, Ablon J, Lapey K.  A double-blind crossover comparison of methylphenidate and placebo in adults with childhood onset ADHD.  Arch Gen Psychiatry. 1995;52(6):434-443; Psychiatry Drug Alerts. 1995;IX(9):71-72.
2. Spencer TJ, Biederman J, Wilens T, et al. A large double blind randomized clinical trial of methylphenidate  in the treatment of adults with ADHD. Biol Psychiatry. 2005;57(5):456-463.
3. Spencer TJ, Biederman J, Mick E, Martin J, Aleardi M. Long term treatment with methylphenidate in adults with ADHD: results from a 6 month study. Poster Presented at: 159th Annual Meeting of The American Psychiatric Association; May 2006; Toronto, Canada.
4. Biederman J, Mick E, Surman C, et al. A randomized, placebo-controlled trial of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2006;59(9):829-35. Epub 2005 Dec 20.
5. Spencer TJ, Adler LA, McGough JJ, Muniz R, Jiang H, Pestreich L; Adult ADHD Research Group. Efficacy and safety of dexmethylphenidate extended-release capsules in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2006 Nov 28; [Epub ahead of print].
6. Adler LA, McGough J, Muniz R, Pestreich L, Agoropoulou C, Jiang H. Long-term efficacy of extended-release dexmethylphenidate in adult ADHD. Presented at: 158th Meeting of the American Psychiatric Association; May 21-25, 2005: Atlanta, Ga.
7. Spencer T, Biederman J, Wilens T, et al. Efficacy of a mixed amphetamine salts compound in adults with attention deficit hyperactivity disorder. Arch Gen Psychiatry. 2001;58:775-782.
8. Weisler RH, Biederman J, Spencer TJ, et al. Mixed amphetamine salts extended-release in the treatment of adult ADHD: a randomized, controlled trial. CNS Spectr. 2006;11(8):625-639.
9. Biederman J, Spencer TJ, Wilens TE, Weisler RH, Read SC, Tulloch SJ. Long-term safety and effectiveness of mixed amphetamine salts extended release in adults with ADHD. CNS Spectr. 2005;10(12 Suppl 20):16-25.



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