Figure 3 Chemical structures of compounds used in the treatment of ADHD.
fewer compliance issues arising from the need for multiple daily dosing, but also provide less potential for diversion and abuse. Shire has transferred two-thirds of the Adderall business to the once-a-day formulation, in spite of the availability of generic forms of Adderall, underlining the importance of once-a-day dosing in this condition. Concerta (J & J) is a novel formulation of methylphenidate designed to provide an initial rapid-release component followed by sustained release. Clinical data demonstrate sustained levels in the efficacious range for approximately 12 h and equivalent or superior efficacy to methylphenidate (4h) on behavioral rating scales.
Common short-term adverse effects, such as appetite suppression, sleep disturbances, and abdominal pain,8'65 are reported with the stimulant class. Longer-term adverse effects are still debated, with reports suggesting motor tic development as well as some height/weight decreases among adolescents with ADHD. While the use of stimulants in children has always been somewhat controversial, recent safety warnings may have a significant impact on future market development. Adderall XR was removed from the Canadian market in 2005 due to an unexpected rate of sudden death and stroke in pediatric patients. The US Food and Drug Administration is currently investigating prior to any final decision on label changes or marketing status. In 2005, warnings of Ritalin links to increased risk of cancer were reported in the US media.
Diversion of stimulant medications continues to be an issue. The medications may be taken orally, or ground into powder and snorted. There are reports of patients selling their stimulant medication to peers for profit, and reports of college students (without ADHD) using methylphenidate or amphetamine recreationally. In addition, the stimulants are contraindicated in patients with a history of illicit use or abuse of stimulants. As new drugs enter the market devoid of abuse liability and not scheduled by the US Drug Enforcement Administration (DEA; see Section 6.05.6.2), it is likely that, if efficacious, these treatments will become the market leaders.
Up to 30% of patients do not respond well to an initial trial of stimulants,83 although approximately 70% of children with ADHD respond to either methylphenidate or dexamphetamine.12 One of the areas where stimulants are most effective is reducing the hyperactivity in ADHD. However, the stimulants are less effective in addressing some of the working memory, organization, and planning (i.e., 'executive function') deficits characteristic of ADHD. Thus, new therapies addressing these other cognitive aspects are likely to be successful in the marketplace. Modafinil (Provigil) is available as Sparlon for the treatment of ADHD in 2006. While modafinil is able to increase extracellular dopamine, it dose not release dopamine in the way that classic stimulants such as amphetamine do. In addition, while there is evidence in nonhuman primates that modafinil is self-administered, modafinil is not DEA-scheduled. Modafinil has been used off-label for the treatment of ADHD, but it is not clear how the approval of this product will change the market.
The first nonstimulant therapy for ADHD, Strattera, rapidly gained acceptance, largely due to its lack of scheduling, low risk for abuse and dependency, nonstimulant side-effect profile (although sleep and growth disturbances are shared with stimulants), and the fact that it was the first indicated product for adults with ADHD. Atomoxetine is a highly specific NET inhibitor, consistent with the likely mode of action described below for the antidepressants and antihypertensive drugs. In addition to efficacy for the treatment of ADHD, atomoxetine has beneficial effects for co-occurring disorders such as anxiety, tics, and depression.
Atomoxetine has similar efficacy and tolerability among adolescents, relative to school-aged children with ADHD. Short-term side effects may include sedation, appetite suppression, nausea, vomiting, and headaches. Atomoxetine also has some cardiovascular liabilities, is slowly metabolized in a subset of patients (because of metabolism via CYP2D6), and has known drug-drug interactions with paroxetine, fluoxetine, albuterol, and other common drugs. In 2005 a warning in bold type of the potential for severe liver injury was added to the label. In contrast to the stimulants, some emerging longer-term side-effect data suggest that normal growth in height and weight is found with atomoxetine treatment.85 Atomoxetine is not scheduled, affording an advantage over stimulant treatment for ADHD. Atomoxetine can be dosed once or twice a day, although the efficacy is not as immediate as found with stimulants, with peak efficacy developing over 2-6 weeks. Physicians may consider Strattera as a second-line therapy behind stimulants because of inferior efficacy, but the lack of scheduling is a key benefit.
Atomoxetine exists as two enantiomers, (R)-(LY-139603) and (S)-(LY-139602). It is selective, does not bind to monoamine receptors, and is devoid of activity for acetylcholine, histamine H1, a1- and a2-adrenergic, and dopamine receptors, allowing a safer profile of action than typical antidepressants. The NET selectivity prompted the testing of atomoxetine in ADHD, since norepinephrine is hypothesized to play a role in the control of sensory processing, with a facilitating action on the dopaminergic system, thought to be impaired in ADHD. The therapeutic utility of atomoxetine underscores the concept that ADHD is not only a disorder of dopamine hypofunction, but has a noradrenergic component, especially for aspects of attention and arousal that are disrupted in ADHD.86
The lack of binding at the monoamine receptors suggests that atomoxetine should have few side effects. In addition, atomoxetine has little effect on the reuptake of dopamine and 5HT, although it binds to a very-low-affinity site, from which it is displaced by citalopram, a selective 5HT reuptake inhibitor SERT.87 In synaptosomal preparations of rat brain, the order of functional potency (Ki value) was 4.5, 152, and 657 nM for norepinephrine, 5HT, and dopamine, respectively. The specificity of atomoxetine for the norepinephrine uptake site is very high, with a Ki for NET inhibition of 0.7-1.9 nM.88
Atomoxetine inhibits norepinephrine uptake in nerve terminals in both the central and peripheral nervous systems. In both pigeons and monkeys, atomoxetine (1-10mgkg_ 1) fully substitutes for the psychostimulants imipramine, cocaine, and methamphetamine, effects blocked by a1-antagonists, further supporting activity of atomoxetine at the norepinephrine receptor. A study using cocaine as the discriminative stimulus in rhesus monkeys, however, failed to demonstrate substitutive properties for atomoxetine.
Another in vivo model that provides evidence of the actions of atomoxetine on the norepinephrine system is the antagonism of cataplexy in the dog, an orexin-deficient canine model of human narcolepsy. Current treatment for narcolepsy includes modafinil, which is the first-line therapy, and combined TCAs and amphetamine-like compounds. Atomoxetine (0.001-1 mgkg "1) is very effective at suppressing cataplexy in the dog - an effect shared by NET inhibitors.
While the nonstimulant component to atomoxetine has permitted differentiation from the stimulant drugs, and initially led to rapid share gains, sales have since reched a plateau, with physicians considering atomoxetine a second-line therapy behind stimulants, primarily because of inferior efficacy and a delayed onset of action. Atomoxetine also has cardiovascular liabilities, is slowly metabolized in a subset of patients (because of metabolism via CYP2D6), and has known drug-drug interactions with paroxetine, fluoxetine, albuterol, and other common drugs. A warning in bold type of the potential for severe liver injury has been added to the label.
Despite these liabilities, atomoxetine is well received in the marketplace, which underscores the importance of lack of scheduling for future treatments of ADHD.
A third line of therapies for ADHD, antidepressants and antihypertensive medications, is not generally approved for use in ADHD, but can be effective off-label. These drugs are sometimes used in combination with stimulants in patients with comorbid symptoms. The antidepressants with demonstrated utility for the treatment of ADHD include the TCAs, bupropion, and monoamine oxidase inhibitors with the antihypertensives, including a2-adrenoceptor agonists.
Imipramine (Figure 3) is a TCA. Imipramine is comprised of a tricyclic nucleus (including two phenyl rings and a central cycloheptadien ring). A short side chain and a terminal amine group are additional structural features characterizing imipramine and related members of the same chemical series.90 The short side chain and the terminal amine group appear to be the conditions that are important for antidepressant activity. The tertiary amines, including imipramine, are more selective for SERT than NET, while the secondary amines, including nortriptyline, are more NET-selective.86
Bupropion hydrochloride (Figure 3) is an aminoketone antidepressant related to the phenylisopropylamines.86 Bupropion appears to act as an indirect dopamine agonist as well as having specific noradrenergic effects, being a functional NET inhibitor.
There is substantial clinical evidence that TCAs have efficacy in ADHD.86 TCAs, including imipramine, desipramine, and nortriptyline, block neurotransmitter reuptake, including norepinephrine. TCAs, while less effective than stimulants for treating cognitive impairments, are effective in controlling behavioral problems and do improve cognitive impairments. Desipramine and nortriptyline have short- and long-term efficacy in adolescents.
It is assumed that the activity of TCAs in the treatment of ADHD stems from actions on reuptake, and in particular norepinephrine reuptake. Advantages of TCAs include their relatively long half-life, up to 12 h, which, as discussed in the stimulant section above, is an important aspect of treatment. Of the studies available investigating the efficacy of TCAs, 91% reported beneficial effects. Interestingly, desipramine has efficacy in placebo-controlled clinical trials in children as well as adults with ADHD.
Antidepressants with dopaminergic modes of action, such as bupropion are also effective and well tolerated in the treatment of ADHD.86 In contrast, SSRIs, which have an improved safety profile, appear to be less effective in treating symptoms of ADHD, although they may be useful in treating common comorbid disorders. Venlefaxine, likely due to its NET inhibition, may have some modest efficacy for ADHD.91 The limited efficacy of SSRIs in ADHD suggests that effects on 5HT may be of less importance than effects on other neurotransmitters, a view supported by lack of efficacy seen with fenfluramine.83 Monoamine oxidase inhibitors are also efficacious in the treatment of ADHD. While a limited number of studies suggest that monoamine oxidase inhibitors may be effective in juvenile and adult ADHD, the side effects (see below) limit their utility.
Although a2-adrenoceptor agonists (clonidine is the most frequently used) have been used in children diagnosed with ADHD, there are few controlled studies supporting efficacy. Clonidine appears to have the greatest benefit in hyperactive and aggressive juveniles.92 A metaanalysis suggests a moderate effect size of clonidine for some co-occurring symptoms of ADHD, including aggression or conduct disorder.92
Concerns regarding the safety of these medications, particularly in children, has limited their use. Common side effects of TCAs among adolescents include sedation, weight gain, dry mouth, constipation, and headache. Three deaths among children with ADHD treatment with desipramine have been reported,46 although the link may not be causal. Heart rate increases are often observed following TCA administration, and thus electrocardiographic monitoring is suggested.
The potential for hypertensive crises associated with tyramine-containing foods (e.g., cheese) and interactions with prescribed, illicit, and over-the-counter drugs limit the usefulness of monoamine oxidase inhibitors in the treatment of ADHD.
The sedative properties of clonidine limit its utility. Sedation is not the basis for the efficacy of clonidine in ADHD, since guanfacine, a more selective a2-adrenergic agonist that produces less sedation, is also effective.46 Although the antihypertensive effects of clonidine appear to be the result of reduced norepinephrine activity (probably through stimulation of presynaptic a2-adrenergic autoreceptors), this is not the likely mechanism of action in ADHD. Instead, studies in monkeys suggest that the effects of a2-adreneceptor agonists on attention are related to stimulation of postsynaptic receptors, particularly in the prefrontal cortex, an area believed to be involved in the pathophysiology of ADHD.93
While side effects limit the utility of many of the antidepressants and antihypertensive agents, Venlafaxine, due to its noradrenergic reuptake inhibition, may have some modest efficacy for ADHD,65 but side effects, including increased hyperactivity, need to be better understood. Several other compounds and medication classes are in development for ADHD (Table 2). Compounds include longer-acting extended-release formulations, such as transdermal methylphenidate (MethyPatch), GABAb antagonists, and selective partial agonists at a4b2 NNRs.
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