new treatment drug for ADHD

new treatment drug for ADHD


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Member #1 | Posted: 20 Apr 2008 12:20:59
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just an apetizer...

NEW TREATMENTS IN ADHD

Oscar G Bukstein, MD, MPH

University of Pittsburgh School of Medicine

INTRODUCTION

Attention deficit hyperactivity disorder (ADHD) is one of the most common problems experienced in youth.(1) Prevalence estimates of ADHD in children of school age have ranged from 2% to 18% in community samples. Of these children, 2.5 million (56%) were believed to be receiving medication for the disorder.(1) Over the past decade, numerous new long-acting formulations of methylphenidate (MPH) and amphetamine (AMP) have provided physicians with additional therapeutic options.

PHARMACOTHERAPY FOR ADHD

The pharmacotherapy for ADHD consists of stimulant and nonstimulant medications. Stimulants are often considered the cornerstone of ADHD treatment. Over the past 3 decades, almost 200 randomized clinical trials of stimulant medications have been performed in patients with ADHD that demonstrate the medications’ efficacy in the treatment of ADHD.(1) Double-blind, placebo-controlled trials in children and adults reveal that up to 75% of subjects with ADHD respond clinically to stimulants, compared with 0% to 30% of subjects treated with placebo. When clinical response is assessed via rating scales, the effect size of stimulant treatment relative to placebo in recent studies is quite large�"in fact one of the largest effects for any psychotropic medication�"according to effect size statistical indices.(1,2,3) However, not all patients with ADHD respond to or tolerate stimulants. The development of nonstimulant agents and the approval by the US Food and
Drug Administration (FDA) of at least one of them has provided physicians with needed alternatives to stimulants.

NEW MEDICATIONS FOR ADHD: STIMULANTS

In the past decade, extensive trials have been carried out on long-acting forms of stimulants, including both MPH and AMP preparations, which are currently approved by the FDA for the treatment of ADHD.(2,3) The MPH preparations include OROS methylphenidate (Concerta), methylphenidate extended-release (Metadate, Ritalin LA), d-methylphenidate (d-MPH) extended-release (Focalin XR), and the MPH transdermal patch (Daytrana). The AMP preparations include the extended-release version of mixed amphetamine salt (MAS XR; Adderall XR) and the prodrug lisdexamfetamine (Vyvanse).

Several differences exist (see Table below) among some of these new formulations and older extended-release preparations such as MPH extended-release (Ritalin-SR), which is a wax-matrix formulation. Metadate CD, Ritalin LA, Focalin XR, and Adderall X are based on a “bead” technology in which long-acting and short-acting beads or portions of beads release the drug so as to mimic bid dosing and extended duration of effect.(2,3) Concerta is based on OROS, an osmotic release system, in which an immediate-release portion of the MPH is in the overcoat of the capsule while the remainder is osmotically released over the course of 9 or more hours.(4)

Additional formulation differences between the newer, long-acting preparations and their predecessors are based on the development of single isomer agents, transdermal patches, and prodrugs. For example, Focalin XR is a single-isomer agent containing d-MPH (the presumed active isomer of MPH), whereas some other MPH agents are racemic mixtures of both the l- and d- MPH isomers. Similarly, Adderall and Adderall XR are mixed amphetamine salts containing both d- and l- AMP isomers, while the older AMP formulations (eg, Dexadrine) contain only d-AMP. In the Daytrana patch (methylphenidate transdermal system), MPH is absorbed through passive diffusion and provides up to 12 hours of efficacy with a 9-hour wear time. Vyvanse (lisdexamfetamine) is a therapeutically inactive molecule (d-AMP covalently bonds to the amino acid lysine) that is converted to its active form by gut enzymes in a presumed rate-limiting process. Given this process, intravenous or
intranasal administration presumably yields minimal stimulant effects, and a possible lower potential for dependence is suggested by studies reporting a significantly lower abuse-related liking effect than an equivalent oral dose of d-AMP.(5,6)

The Table below provides the mean duration of the various formulations. All of these preparations are marketed as extended-release and “once-daily” medications. Based on analog classroom data, Concerta, Focalin XR, Daytrana, and Vyvanse all show efficacy at 12 hours following administration.(2,3) These agents show comparable levels of efficacy in terms of the decrease in and control of ADHD symptoms.(2,3) Extended-release formulations have been shown to be efficacious in adolescents as well as children, as they offer greater convenience for the patient and family and enhanced compliance and confidentiality.

Adverse effects of extended-release formulas are similar across formulations and similar to immediate-release stimulants.(2,3) However, largely because of the absence of head-to-head studies between these agents, the clinical significance of these variations in formulations in terms of comparative efficacy and safety is not known.

NEW MEDICATIONS FOR ADHD: NONSTIMULANTS

Atomoxetine is a noradrenergic reuptake inhibitor shown to be superior to placebo in the treatment of ADHD in children, adolescents, and adults. It is the first and only nonstimulant medication approved by the FDA for the treatment of ADHD and is approved for use in children, adolescents, and adults.(7) Unlike stimulants in general, atomoxetine can be given in the late afternoon or evening.(7) Atomoxetine may also have less pronounced effects on appetite and sleep than stimulants, although it may produce relatively more nausea or sedation.(7) Atomoxetine has been studied in the treatment of patients with ADHD and comorbid anxiety. At the end of a 12-week treatment period, atomoxetine led to a significant reduction in the symptoms ratings of both ADHD and anxiety relative to placebo, showing the drug to be potentially efficacious in the treatment of both conditions.(7)

Modafinil is currently marketed as Provigil for patients with narcolepsy, sleep apnea, and shift work sleep disorder, but it has been demonstrated to be efficacious in the treatment of ADHD in children of school age. The most commonly reported adverse effects in the modafinil group were insomnia (29%), headache (20%), and decreased appetite (16%).(8) The presence of a possible case of Stevens-Johnson syndrome prevented FDA approval.(8)

Guanfacine extended-release (XR), tentatively named Intuniv, is a selective alpha-2A-adrenoceptor agonist. Data from 2 short-term, phase III, placebo-controlled studies and 2 long-term, phase III, open-label studies demonstrated that guanfacine XR significantly improved all core symptoms of ADHD in children aged 6-17 years.(9) Guanfacine XR has received an approvable letter from the FDA, and marketing of this agent is expected in 2009.(10)

SELECTING THE “RIGHT” MEDICATION OR FORMULATION

The initial pharmacological treatment of ADHD should be a trial with an agent approved by the FDA for the treatment of ADHD. Direct comparisons of atomoxetine with MPH and AMP have shown greater treatment efficacy with the stimulants, although the studies were of short duration.(1) Of note, atomoxetine may be considered a first-line medication for ADHD in patients with an active substance abuse problem, comorbid anxiety or tics, or an intolerance of stimulants because of adverse effects.(1)

Overall efficacy and adverse effects are similar across stimulants; therefore, physicians can use their discretion when selecting a medication. For young children or others unable to swallow pills or capsules, the MPH transdermal patch and bead preparations, which allow one to open the capsules and sprinkle the beads on food, offer an alternative that may improve compliance. In addition, the prodrug lisdexamfetamine may offer a lower potential for dependence. Furthermore, while a number of agents are once-a-day preparations, some individuals may prefer a shorter-acting agent because of personal preference or a pattern of adverse effects.

Not all patients with ADHD respond to any one medication, and response prior to a trial of medication cannot be clearly predicted. For some, sequential trials with various stimulants or nonstimulant agents or formulations may be necessary to achieve an adequate or, preferably, optimal response.

REFERENCES

1. Dulcan M. Practice parameters for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder. American Academy of Child and Adolescent Psychiatry (AACAP). J Am Acad Child Adolesc Psychiatry. 1997;36(10):85S-121S.

2. Newcorn JH, Ivanov I. Psychopharmacologic treatment of attention-deficit/hyperactivity disorder and disruptive behavior disorders. Pediatric Annals. 2007;36(9):564-74.

3. Pliszka SR, Crismon ML, Hughes CW, et al. The Texas Children’s Medication Algorithm Project: revision of the algorithm for pharmacotherapy of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2006;45(6):642-57.

4. Wolraich ML, Greenhill LL, Pelham W, et al. Randomized, controlled trial of oros methylphenidate once a day in children with attention-deficit/hyperactivity disorder. Pediatrics. 2001;108(4):883-92.

5. Biederman J, Krishnan S, Zhang Y, McGough JJ, Findling RL. Efficacy and tolerability of lisdexamfetamine dimesylate (NRP-104) in children with attention-deficit/hyperactivity disorder: a phase III, multicenter, randomized, double-blind, forced-dose, parallel-group study. Clinical Therapeutics. 2007;29(3):450-63.

6.. Jasinski D, Krishnan S, Kehner G. Abuse liability of intravenous lisdexamfetamine (LDX; NRP-104). Presented at the 2006 Annual Meeting of the Society for Developmental and Behavioral Pediatrics; September 17, 2006; Philadelphia, Pennsylvania.

7. Michelson D, Allen AJ, Busner J. Once-daily atomoxetine treatment for children and adolescents with attention deficit hyperactivity disorder: a randomized, placebo-controlled study. Am J Psychiatry.. 2002;159(11):1896-901