Treatment of ADHD

Pemoline [2152-34-3] (24), stmcturally dissimilar to amphetamine or methylphenidate, appears to share the CNS-stimulating properties. As a consequence, pemoline is employed in the treatment of ADHD and of narcolepsy. There are several other compounds that are stmcturally related to amphetamines, although not as potent and, presumably, without as much abuse potential. These compounds also have anorexic effects and are used to treat obesity. Some of the compounds available are phentermine [122-09-8] fenfluramine [458-24-2] and an agent that is available over-the-counter, phenylpropanolamine [1483815-4] (26). 

The most common treatment of ADHD is pharmacological. Psychostimulant diugs such as methylpheni-date and amphetamine or atomoxetin, an inhibitor of the noradrenaline transporter can be prescribed. These agents elicit the non-exocytotic release of... 

Grace AA (2001) Psychostimulant actions on dopamine and limbic system function relevance to the pathophysiology and treatment of ADHD. In Solanto MV, Arnsten AFT, Castellanos FX (eds) Stimulant drugs and ADHD, Oxford University Press, pp 134—157... 

Atomoxetine (9), a selective NRI, is the first non-stimulant drug approved for the treatment of ADHD [22]. Interestingly, in a recent 12-week, randomized, double blind, placebo-controlled trial in 30 obese women, atomoxetine demonstrated modest short-term weight loss efficacy relative to placebo [23]. 

Of greater concern is the safety of the TCAs. Toxic levels of these medications can produce lethal cardiac arrhythmias, seizures, and suppression of breathing. An overdose of a 1-2 week supply of most TCAs is often fatal, a serious consideration when prescribing medication to depressed patients with suicidal thoughts. Children taking imipramine for treatment of ADHD have died from sudden cardiac death consequently, child psychiatrists seldom use TCAs. Likewise, patients with heart disease or seizure disorders are more likely to have dangerous complications from TCAs and should avoid them. 

Althongh some gronps have used the controversy snrronnding ADHD as a platform to attack the nse of psychiatric medications as a whole, we should not in onr haste to dismiss snch perspectives overlook the fact that these are fair and reasonable qnestions. For that reason, we will try in this chapter to address these questions as we discnss the diagnosis, the long-term conrse, and the treatment of ADHD. The treatment options have recently expanded with the FDA approval of atomoxetine (Strattera), a selective norepinephrine renptake inhibitor that is not a psychostimn-lant, for the treatment of ADHD. 

Methylphenidate (Ritalin). Methylphenidate was developed in the late 1950s and its first use was the treatment of what we now call ADHD. Since that time, it has also been approved for the treatment of narcolepsy. Its only other use is the treatment of severe refractory depression either in medically ill patients who need rapid clinical improvement or as an augmentation agent when added to other antidepressants. In the treatment of ADHD, methylphenidate not only improves attention but also reduces hyperactivity and impulsivity. Verbal and physical aggression typically decreases as well. 

Dextroamphetamine (Dexedrine). Dextroamphetamine is the second most widely used stimulant and the most commonly used amphetamine in the United States. It is about twice as potent as methylphenidate and should be initiated in the treatment of ADHD at 2.5 mg taken twice daily with breakfast and lunch. Like other stimulants, the benefits of dextroamphetamine can be seen almost immediately. With weekly visits while starting treatment, the dose can be increased in 2.5-5 mg increments until the effective dose is found. Because dextroamphetamine is also slightly longer acting than methylphenidate, patients may be less likely to need an evening dose. If an after-school dose is used, then like methylphenidate it should be 25-50% of the daytime dose. 

Modafinil (Provigil). The newest stimulant, modafinil, is not, pharmacologically, a true stimulant. Nevertheless, it is an effective treatment for narcolepsy at doses from 200 to 400mg/day. Several studies indicate that modahnil has little potential for abuse and is easier to tolerate than other stimulants. Modafinil has been studied in the treatment of ADHD. Though not approved for marketing by the FDA at the time of this writing, it may gain the indication in the near future. 

Serotonin-Boosting Antidepressants. Antidepressants that enhance serotonin activity in the brain have also been studied in ADHD. In particular, fluoxetine (Prozac) and the serotonin-selective TCA clomipramine (Anafranil) have been the most extensively evaluated, with mixed success. They provide some benefit for aggression and impulsivity but don t significantly improve the poor attention of ADHD. As a result, the SSRls and other serotonin-boosting antidepressants do not appear to be effective first-line treatments for ADHD. Conversely, depressed patients without ADHD often show improvements in symptoms of concentration and attention when treated with a SSRI. Although SSRls are not widely used in the treatment of ADHD, they may be worthy of consideration in ADHD patients whose impulsivity is not controlled by stimulants alone. Those with comorbid conduct disorder or ODD who are prone to agitation and at times violent outbursts may be helped by the addition of a SSRI. 

Antipsychotics also have a troublesome side effect burden that includes an often-irreversible movement disorder known as tardive dyskinesia (TD). Other side effects include so-called parkinsonism, dystonic reactions (i.e., abrupt onset of muscle spasms), akathisia (an uncomfortable sense of motoric restlessness), sedation, weight gain, dizziness, dry mouth, and constipation among others. These side effects, in particular the risk for TD, limit the usefulness of antipsychotics in the treatment of ADHD, and at this time the typical antipsychotics cannot be considered a reasonable monotherapy in uncomplicated ADHD. 

Atypical Antipsychotics. The so-called atypical antipsychotics are not well studied in the treatment of ADHD. However, a few case reports have indicated that risperidone (Risperdal) may reduce the impulsivity and hyperactivity of ADHD. There is also preliminary evidence that risperidone may be effective in treating tics. Although the usefulness of risperidone and other atypical antipsychotics in treating ADHD needs more study, this may prove another viable treatment alternative for patients with ADHD and tics or agitation. 

Attention deficit hyperactivity disorder (ADHD) For the treatment of ADHD in patients 6 years of age and older. Dexmethylphenidate is indicated as an integral part of a total treatment program for ADHD that may include other measures (eg, psychological, educational, social) for patients with this syndrome. Drug treatment may not be indicated for all patients. Stimulants are not intended for use in the patient who exhibits symptoms secondary to environmental factors or other primary psychiatric disorders, including psychosis. 

Attention-deficit/hyperactivity disorder (ADHD) For the treatment of ADHD. 

Maintenance treatment There is no evidence available from controlled trials to indicate how long the patient with ADHD should be treated with atomoxetine. However, pharmacological treatment of ADHD may be needed for extended periods. Periodically re-evaluate the long-term usefulness of the drug for the individual patient. 

As of 2006, there are several branded medications approved for the treatment of ADHD however, there are only three chemicals that make up the primary active ingredients in these drugs the (5)-enantiomer of amphetamine (1), the 2(/ ),2 (7 )-enantiomer of methylphenidate (2), and the (/ )-enantiomer of atomoxetine (3). An older approved ADHD drug, pemoline (Cylert ), was withdrawn from the market in 2005 due to reported... 

Stimulant treatment of ADHD has generated the largest body of treatment literature of any childhood psychiatric disorder. Between 1962 and 1993, over 250 reviews and over 3000 articles were published on stimulant effects (Swanson, 1993). By 1996, 161 randomized controlled trials (RCTs) had been published, encompassing 5 preschool, 150 school-age, 7 adolescent, and 9 adult studies. Improvement occurred in 65 %-75% of the children randomized to stimulants (meth-ylphenidate) [MPH] n = 133 trials dextroamphetamine [DEX] n = 22 trials pemoline [PEM] n = 6 trials) compared to 5%-30% of those assigned to pla-... 

Jensen, P., Kettle, L., Roper, M., Sloan, M., Dulcan, M., Hoven, C., Bird, H., Bauermeister, J., and Payne, J. (1999) Are stimulants overprescribed Treatment of ADHD in 4 US communities./ Am Acad Child Adolesc Psychiatry 38 797-804. 

TACT Study Group, (2002) Treatment of ADHD in children with Tourette s syndrome (TACT Trial). (2002), in press. 

Swanson, J.M., Flockhart, D., Udrea, D., Cantwell, D.P., Connor, D., and Williams, L. (1995) Clonidine in the treatment of ADHD questions about safety and efficacy. / Child Adolesc Psychophar-macol 5 301-304. 

Inhibition of the MAO-A enzyme for the treatment of depression is appealing because MAO-A is specifically responsible for the degradation of serotonin and norepinephrine. There was initial interest in clorgyline for treatment of adult depression and childhood ADHD (Potter et ah, 1982 Zametkin et ah, 1985). Clorgyline was found to be beneficial in a small, double-blind, crossover study for the treatment of ADHD in children, but adverse events associated with irreversibility resulted in the lack of an industry sponsor for further trials (Zametkin et ah, 1985). 

The Multimodal Treatment of ADHD (MTA) Study, a large, multisite study of ADHD treatment (MTA Cooperative Group, 1999), highlights the importance of this therapeutic alliance. When outcome was measured only in terms of the child s inattention, stimulant medication alone did as well as medication plus psychosocial treatment. However, the combination of medication and psychotherapy had the best outcome in parent satisfaction and in reducing disruptive behaviors (Hinshaw et ah, 2000), which are important factors in longer-term compliance with treatment and outcome. 

In open studies of adult ADHD, moderate improvements were reported in studies with pargyline and selegiline (MAOI-Bs) (Wender et ah, 1983, 1985). In a controlled study of selegiline in adult ADHD (Ernst 1996), use of active drug failed to produce results different from those with placebo however, the placebo response was unusually high in that study. In addition, a high dose (60 mg) was more effective than a low dose (20 mg), which suggests that MAOI-A effects may be more helpful in the treatment of ADHD. 

As may be expected, studies of antidepressants in treatment of ADHD have not shown a differential effect in ADHD children with or without conduct disorder, depression, or anxiety (Biederman et ah, 1993b). While DMI-treated ADHD children showed a substantial reduction in depressive symptoms compared with placebo-treated patients (Biederman et ah, 1989), DMI appears not to be as powerful an antidepressant in children as the SSRls. (Bostic et ah, 1999). The safety and efficacy of combined SSRl and stimulant pharmacotherapy has been addressed in two open studies and is currently being evaluated in a prospective study conducted by the Resarch Units in Pediatric Psychopharmacology (RUPP) Network (B. Vitiello, personal communication). 

Despite a large body of literature documenting the effectiveness of medication in the treatment of ADHD, there has been public and professional concern regarding the possible inappropriate diagnosis and prescrip-... 

Castellanos, F.X., Giedd, J.N., Elia, J., Marsh, W.L., Ritchie, G.F., Hamburger, S.D., and Rapoport, J.L. (1997) Controlled stimulant treatment of ADHD and comorbid Tourette s syndrome effects of stimulant and dose. / Am Acad Child Adolesc Psychiatry 36 589-96. 

Schachar, R., Tannock, R., Cunninggham, C., and Corkum, P. (1997) Behavioral, situational, and temporal effects of treatment of ADHD with methylphenidate. J Am Acad Child Adolesc Psychiatry 36 754-763. 

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