Nonstimulant Medications for ADHD

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Although stimulant medications are effective in alleviating ADHD symptoms in most children, adolescents, and adults who suffer from the disorder, about 20 to 30 percent do not respond well to stimulants. For these individuals, nonstimulant medications may be effective. Even among those who do experience significant relief from their symptoms when taking stimulants, there are many who experience significant difficulties with mood, anxiety, tics, or other problems that may be exacerbated, or at least not helped much, by stimulants. For these individuals, too, treatment with nonstimulant medications may be preferable. This chapter does not provide an exhaustive review of all nonstimulant medications used for treatments of ADHD; only those prescribed most often are listed here.

Atomoxetine

At present only one nonstimulant medication, Atomoxetine (ATX), has been approved by the FDA specifically for treatment of ADHD. (Nonstimulant medications approved for other uses are often used for ADHD treat ment; they are discussed later.) Approved in November 2003, ATX has already been subjected to extensive testing. In controlled scientific studies including over 1,600 individuals, ATX has been demonstrated to be safe and effective as a treatment for ADHD in children, adolescents, and adults.

Marketed under the brand name Strattera, ATX is not a stimulant. Unlike stimulants it is not classified as a "Schedule II" medication; that is, it has very low potential for abuse and is not subject to the strict rules enforced for stimulants, pain medications, and other compounds that, if misused, could cause addiction. This means that ATX can be obtained more conveniently by patients. Physicians can provide samples, can phone prescriptions to the pharmacy, and can provide refills without having to write a new prescription each time.

ATX takes a different approach than stimulants to alleviating the impairments of ADHD. While stimulants target primarily the dopamine system in the brain, ATX targets primarily the noradrenergic neurotransmitter system. ATX helpfully slows the reuptake of norepinephrine at noradre-nergic synapses in the brain in much the same way that stimulants helpfully slow transmitter reuptake in synapses of the dopamine system. As described in Chapter 3 of this book, the noradrenergic and dopaminergic systems are the two neurotransmitter systems most involved in management of executive functions impaired in ADD syndrome. The relative influence of each of these two systems on specific aspects of ADHD impairments has not yet been determined.

Adequate "head-to-head" research has not yet tested whether ATX provides the same degree of improvement for inattention symptoms of ADHD as the stimulants usually do. But clinical trials have clearly shown in sizable groups of children, adolescents, and adults that, for many, this medication can significantly alleviate both inattention and hyperactive or impulsive symptoms of ADHD. In addition, ATX has the advantage of lasting longer than stimulants. Some parents report that while on ATX their ADHD children are easier to get along with throughout the day and evening, are able to fall asleep with less difficulty at bedtime, and are able to awaken the next morning with less irritability and oppositional behavior. There is also some evidence that ATX may help to alleviate the anxi ety and depressive symptoms that often appear with ADHD and are less likely to be alleviated by stimulants.

One disadvantage of ATX is that it does not provide noticeable benefits until the patient has been taking it daily for three to five weeks. By comparison, stimulants are usually noticeably effective within an hour after the patient has ingested a dose that is of optimal strength for them. Common side effects of ATX may include stomachache (especially if taken on an empty stomach) and drowsiness; usually these gradually diminish after a few days or weeks on the regimen. Another disadvantage is that the capsules should be swallowed whole; but this is usually a problem only for very young children who are unable or unwilling to swallow a pill.

The dopaminergic and noradrenergic systems both contribute to the biological elements underlying ADD syndrome. And individuals with ADD syndrome vary considerably in which aspects of the ADD syndrome are most problematic for them. Given these factors, it is likely that some patients with ADD syndrome will respond better to ATX than to stimulants while others will respond better to treatment with a stimulant. Unfortunately, there is not yet a sufficient base of research and clinical experience for clinicians reliably to predict which of these medications will be most helpful to any particular patient. Clinical experience and research should eventually yield useful guidelines for such decisions.

While it is usually preferable to treat ADD syndrome with just one medication, there may be some circumstances where neither stimulants nor ATX alone provide adequate alleviation of an individual's impairment from ADD syndrome. In such cases, carefully combined use of these two medications might be considered. In 2004, I presented case reports on the successful use of ATX and stimulants in combination for some patients who did not respond adequately to either agent alone. Yet I cautioned that there is not yet research to guide such combined use, so very careful clinical monitoring is essential.

While ATX is the only nonstimulant medication thus far approved by the FDA specifically for treatment of ADHD, a number of other nonstim-ulant medications have been demonstrated helpful for treatment of the disorder. Guidelines from the American Academy of Pediatrics (2001) iden tified tricyclic antidepressants and buproprion as "second-line agents" for treatment of ADHD. Clinicians are advised to utilize second-line agents for ADHD only if an individual fails to respond adequately to adequate trials of at least two stimulants and ATX.

Tricyclic Antidepressants

Tricyclic antidepressants (TCAs) were introduced in the late 1950s as an effective treatment for major depression. Medications in this class include imipramine, desipramine, nortriptyline, and others; all act primarily on the noradrenergic system. TCAs remained the primary agents for treatment of depression until the advent of selective serotonin reuptake inhibitors in 1987. Most of the research on use of TCAs for treatment of ADHD has focused on desipramine and nortriptyline.

These medications have the advantage of lasting relatively long, so they do not require multiple daily doses and do not produce the "hills and valleys" or "rebound" effects sometimes found in treatment with stimulants. They tend to be quite effective in alleviating hyperactive and impulsive symptoms of ADHD, though they have not generally been found to improve the inattention symptoms of ADHD as much as do the stimulants. TCAs tend to be especially helpful for ADHD patients who suffer from comorbid depression, anxiety, oppositionality, or tics.

Timothy Wilens and colleagues (2002) recommended that dosing with TCAs should start with 25 mg daily with a gradual increase to a maximum of 5 mg per kg of patient weight per day, except for nortriptyline, whose dosing should be limited to a maximum of 2 mg per kg per day. Often responses to TCA treatment are not very noticeable until the regimen has been continued for three to five weeks. Adverse effects with TCAs may include sedation, weight gain, dry mouth, constipation, and sexual dysfunction. Usually nortriptyline produces fewer adverse effects than do the other TCAs.

The primary disadvantage of TCAs is their relatively narrow margin of safety. If these medications are taken in a significant overdose, accidental or deliberate, they can cause severe, even fatal, cardiovascular problems. This is an important risk factor, especially in households with young children or for individuals with depressive problems. Despite a substantial body of research showing the effectiveness of desipramine for treatment of ADHD, many physicians stopped prescribing it, at least for pre-pubescent children, after sudden deaths were reported in four children who had been taking appropriate, not excessive, doses of desipramine for ADHD. Joseph Biederman and others (1995a) have reported that the risk of sudden death when taking appropriate doses of desipramine is elevated only slightly above the normal risk for sudden, unexplained death in children. Nevertheless, caution is advised when considering this specific medication for prepubescent children. For ADHD most clinicians feel more comfortable prescribing nortriptyline because it tends to have fewer adverse effects than most other TCAs.

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