Manifestation of Adult Attention-Deficit/Hyperactivity Disorder: Pharmacological Therapy
A wealth of evidence supports the use of stimulants in the treatment of ADHD in children. According to the evidence-based clinical practice guideline for outpatient evaluation and management of ADHD produced by the Cincinnati Children’s Hospital Medical Center, stimulants are first-line therapy in treatment plans requiring medications in children with ADHD. Stimulants approved for the treatment of ADHD in children include:
- methylphenidate (Concerta, Alza/McNeil Consumer; Daytrana patch, Shire; Focalin and Focalin XR, Novartis; Metadate CD, Metadate ER, Celltech; Methylin and Methylin ER, Mallinckrodt; Ritalin, Ritalin SR, Ritalin LA, Novartis).
- amphetamine salts (Adderall, Adderall XR, Shire).
- dextroamphetamine (Dexedrine, GlaxoSmithKline; Dextrostat, Shire).
- methamphetamine (Desoxyn, Ovation).
- pemoline (Cylert, Abbott).
Relatively little evidence exists, however, to support the use of these drugs in the treatment of adults with ADHD.
Several published studies have examined the effectiveness of methylphenidate (MPH) for adult ADHD, but the findings vary widely. In a sample of 23 adults with ADHD, Spencer et al. found an average response rate of 78% among subjects receiving MPH compared with 4% for placebo (P < .0001) in a seven-week, double-blind, placebo-controlled, crossover study. In a study of similar design and sample size, Mattes et al. found that only 25% of those treated with MPH showed a clinical benefit.
Other trials have demonstrated response rates with MPH within this wide range of values. Wender et al. found a 57% moderate-to-marked therapeutic response rate;12 Shekim et al., a 70% response rate; and Wood et al., a 73% rate. Kooij et al. also observed a variable response rate between 38% and 51% for MPH, compared with a range of 7% to 18% for placebo (P < .05).
Overall, large, rigorous trials examining the efficacy of MPH for the treatment of adult ADHD are lacking. Most of the existing studies are small, and they vary widely in duration, diagnostic criteria, outcome measures, and indicators of response, not to mention overall response rates.
More recently, Spencer et al. published the results of a large, double-blind, randomized clinical trial of MPH in adult ADHD. To date, this is the largest study examining stimulant medications for adult ADHD available in the literature. A total of 146 subjects were assigned to receive either MPH or placebo. The investigators used the Clinical Global Impression (CGI) scale and the Adult ADHD Investigator System Report Scale to assess response to MPH treatment. Overall, they found a marked therapeutic response for MPH in the treatment of ADHD symptoms (76%) that exceeded the placebo response (19%) (P < .0001).
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Despite the lack of conclusive evidence supporting MPH in adult ADHD, even fewer studies have evaluated the efficacy of amphetamine salts. In a seven-week, double-blind, placebo-controlled, crossover study, Spencer et al. found that 70% of those treated with amphetamines demonstrated a reduction on the ADHD Rating Scale of at least 30%, compared with only a 7% response rate with placebo (P = .001). The investigators also noted a dose relationship along a daily dose range of 20 to 60 mg.
In an open-label trial of low-dose amphetamine salts (10 mg), Horrigan and Barnhill observed a slightly lower response rate of 54% based on the CGI scale. Even though it might not be appropriate to compare the results of these studies— because the outcomes were based on different measurement tools—the lower response rates that they documented are consistent with the findings of a clear dose relationship, as suggested by the Spencer study. It is important to note that the Horrigan and Barnhill study was not placebo-controlled.
The prescribing information for amphetamine salts cites a double-blind, randomized, placebo-controlled, parallel-group study of 255 adults with ADHD. This would clearly be the largest such trial examining the safety and efficacy of any stimulant medication in the treatment of adult ADHD, but the study has not been published.
As indicated in the prescribing information, the results suggest that significant improvements in ADHD symptoms occurred with amphetamine salts, compared with placebo, based on the ADHD Rating Scale. Subsequent to these findings, the U.S. Food and Drug Administration (FDA) has approved amphetamine salts for the treatment of ADHD in adults. Apcalis Oral Jelly
Only two published studies have examined the use of dex-troamphetamine for adult ADHD. In one study, Taylor and Russo compared dextroamphetamine with guanfacine (Tenex, A.H. Robins), an alpha-2a agonist. The double-blind, placebo-controlled, crossover study suggested a similar response to the drugs. However, because the efficacy of these two drugs had not been previously established in this population, it is not known how these drugs compare with placebo.
In the second trial, the same investigators enrolled 22 adults in a randomized, double-blind, placebo-controlled crossover study to compare dextroamphetamine with modafinil (Provigil, Cephalon) and with placebo. Both dextroamphetamine and modafinil led to improved scores on the DSM-IVADHD Checklist, with statistical significance over placebo (P < .001). The results suggested that both agents might, in fact, have beneficial effects in adults with ADHD.
A paucity of evidence exists for the use of pemoline (Cylert, Abbott) in adults with ADHD, but overall, response rates are lower than those of other stimulant medications. On October 24, 2005, the FDA issued an alert stating that the overall risk of liver toxicity from pemoline outweighed the benefits of this drug. Several months earlier, Abbott chose to stop sales and marketing of the drug in the U.S, as did all manufacturers of the generic brands.
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Summary of the Stimulants
Additional rigorous, randomized controlled trials with large sample sizes, a standardized diagnosis, and standardized measures of response are necessary to fully understand the impact of stimulant medications on ADHD in adults. Furthermore, recent problems regarding the risk of cardiovascular effects and psychosis associated with stimulants have raised safety concerns. On February 9, 2006, the FDA’s Drug Safety and Risk Management Advisory Committee voted to recommend a “black-box” warning describing the cardiovascular risks of stimulants in the treatment of ADHD. On March 3, 2006, the FDA issued a memorandum regarding the incidence of psychiatric adverse events associated with ADHD medications based on postmarketing safety data. The 94-page publication describes a multitude of case reports suggesting a link between these medications and events such as psychosis, sui-cidality, aggression, violent behavior, and mania. Additional common side effects of the drugs reviewed in this article are listed.