Stimulants for ADHD

Eli Lilly promoted and continues to promote Strattera as the nonstimulant drug to treat ADHD (Eli Lilly and Company, 2006). While the company maintains this position, the drug is nonetheless listed under Central Nervous System Stimulants in the Physicians Desk Reference (2007, p. 208). Lilly s extremely shrewd marketing ploy of promoting Strattera as a nonstimulant is meant to allay the concerns of parents and doctors about their children taking stimulants for ADHD. 

Box 8.1 Factors to consider before prescribing stimulants for ADHD... 

Atomoxetine is the most recent addition to the ADHD armamentarium in both children and adults. In clinical studies, atomoxetine has demonstrated superior efficacy over placebo and equivalent efficacy when compared with a suboptimal immediate-release methylphenidate dose.17 20 However, it is not clear whether atomoxetine is superior to typical methylphenidate doses or other stimulant formulations. Atomoxetine may be used as a second- or third-line medication for ADHD. 

The tricyclic antidepressants (TCAs), such as imipramine, can alleviate symptoms of ADHD. Like bupropion, TCAs likely will improve symptoms associated with comorbid anxiety and depression. The mechanism of action of TCAs is in blocking norepinephrine transporters, thus increasing norepinephrine concentrations in the synapse the increase in norepinephrine is believed to alleviate the symptoms of ADHD. TCAs have been demonstrated to be an effective non-stimulant option for ADHD but less effective than stimulants. However, their use in ADHD has declined owing to case reports of sudden death and anticholinergic side effects6,13 (Table 39-3). Further, TCAs may lower seizure threshold and increase the risk of car-diotoxicity, (e.g., arrythmias). Patients starting on TCAs should have a baseline and routine electrocardiograms. 

Methamphetamine (Desoxyn). Methamphetamine is a relatively long-acting stimulant. Lasting up to 12 hours, it can often be taken only once a day and is just as effective at treating ADHD as other stimulants. However, methamphetamine is seldom used today. For one thing, it is much more expensive than other stimulants. For another, this variant of amphetamine is the form often produced in illicit speed labs for street use. Many families and physicians are understandably reluctant to use a medication with this reputation for abuse. 

Bupropion (Wellbutrin, Zyban). Bupropion is a newer atypical antidepressant that was initially suggested to increase both norepinephrine and dopamine activity in the brain, though controversy surrounds this hypothesis. Although bupropion has not been studied extensively in ADHD, early evidence does indeed indicate that it may be effective for both inattention and hyperactivity/impulsivity. Its effectiveness for ADHD does not appear to rival the stimulant medications, though a recent controlled study for adult ADHD showed that bupropiou outperformed placebo. 

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. 

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. 

The most common treatments for ADHD are the stimulant medications methylphenidate and amphetamines. Secondary medications include dopaminergic or noradrenergic reuptake blockers (e.g., a tamoxetine) and ttj-adrenergic agonists. These treatments are reviewed in this volume (see Chapters 20, 21, 24, and 35). Thus, only brief reference will be made here to the possible effects these compounds may have vis-a-vis modulation of attentional circuits. These ideas are summarized in Figure 8.2. 

In the United States, clinicians have steadily increased their stimulant prescribing over the past decade. Outpatient visits to primary practitioners for ADHD-related problems have increased from 1.6 to 4.2 million per year between 1990 and 1993 (Swanson et ah, 1995). During these visits, 90% of the children were given prescriptions, 71% of which were for the stimulant MPH. Further evidence of increased stimulant use is that MPH production in the United States increased from 1784 kg/year to 5110 kg/year during the same 3-year period. Over 10 million prescriptions for MPH were written in 1996 (Vitiello and Jensen 1997). 

Heiligenstein, J.H., Spencer, T, Paries, D., Biederman, J, and Conners, C.K. (2000), Tomoxetine, a non-stimulant, noradrenergic enhancer for ADHD, doubleblind treatment results. In Annual Meeting of the American Academy of Child and Adolescent Psychiatry New York The American Academy of Child and Adolescent Psychiatry. 

Tricyclic antidepressants (TCAs) are not as well studied as stimulants for treatment of ADHD even in normally developing children and adolescents, but are well enough studied that they are established as a second-line treatment. There are no controlled studies of TCAs in MR. Two case series reported ADHD symptom improvement, but seizures were a problem in one series (Szymanski, 1998). 

We recently surveyed pharmaceutical companies producing antidepressant medication or central nervous system (CNS) stimulants for the European market. Approval for use of such drugs in children and adolescents is limited worldwide. Sertraline, clomipramine, and flu-voxamine have been approved for use in children (for some drugs down to the age of 6 years) for OCD in some European countries (the most wide spread approval being for sertraline in Austria, France, Hungary, Italy, Latvia, Norway, Portugal, Romania, Slovenia, Spain, Sweden, Switzerland, Turkey, United Kingdom, and Denmark) and countries outside Europe. Methyl-phenidate has been approved for the treatment of children with ADHD in a number of European and non-European countries (Novartis Health care A/S, personal communication). 

Biederman, J. and Spencer, T. (2000) Non-stimulant treatments for ADHD. Eur Child Adolesc Psychiatry 9 51—59. 

Methylphenidate hydrochloride, a piperidine derivative structurally similar to amphetamine, is a commonly prescribed stimulant for the treatment of ADHD in children age 6 years and older. It is a racemic mixture of d,l methyl a-phenyl-2-piperidineacetate hydrochloride. The drug is available in immediate-release, extended-release, and controlled-release formulations. It is hepatically metabolized to an inactive metabolite and excreted by the kidneys. 

Strattera (package insert). Indianapolis, IN, Eli Lilly and Co, 2005 Swanson JM, Volkow ND Pharmacokinetic and pharmacodynamic properties of stimulants implications for the design of new treatments for ADHD. Behav Brain Res 130 73-78, 2002 Swanson J, Gupta S, Lam A, et al Development of a new once-daily formulation of methylphenidate for the treatment of attention-deficit/hyperac-tivity disorder proof of concept and proof of product studies. Arch Gen Psychiatry 60 204-211, 2003... 

As of 2001, the U.S. Food and Drug Administration (FDA) approved the use of stimulants for treating atten-tion-deficit/hyperactivity disorder (ADHD), narcolepsy, and Parkinson s disease. These drugs are also used in combination with other medications to manage pain, and to treat depression and other psychiatric disorders. 

The National Institute on Drug Abuse (NIDA) estimates that there were approximately 900,000 Americans age 12 and older misusing prescription stimulants in 1999. Because of its popularity as a treatment for ADHD, adolescents are at a special risk for misusing dextroamphetamine drugs. 

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