Adderall: Efficacy and Safety for ADHD Adolecents
Attention Deficit Disorder with Hpyeractivity is a developmental disorder that can is generally diagnosed in childhood and can persist into adulthood. Adderall is a stimulant that is typically used to treat ADHD. A newer version Adderall XR hit the market in 2001 and a generic form was released in 2009. This paper reviews the study: “Efficacy and Safety of Mixed Amphetamine Salts Extended Release (Adderall XR) in the Management of Attention-Deficit/Hyperactivity Disorder in Adolescent Patients: A 4-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study” done in 2006. This paper hopes to clarify the internal and external validity of the study and the significance the study has for ADHD populations.
Adderall and Ritalin are central nervous system stimulants that affect the brain and nerves that contribute to hyperactivity and impulse control. These drugs, along with psychotherapy, are generally used in the treatment of Attention Deficit Disorder with Hyperactivity (ADHD). ADHD is a developmental disorder typically first identified in childhood that has been demonstrated to persist into adulthood (Brown & Rosa, 2002). It is a disorder of inadequate response inhibition, a problem of performance (not skills) and of inconsistency (not inability) (Goldstein & Naglieri, 2008).The prevalence of the disorder is estimated to range from 2% to 18% in US children and adolescents (Meaux et al., 2006). Symptoms include difficulty staying focused and paying attention, difficulty controlling behavior, and hyperactivity (over-activity) (NIMH, 2008). Children often struggle with following through on their homework and can be disruptive during classroom activities. As ADHD persists into adulthood many adolescents and young adults are may become discouraged by doing poorly in school. Teens may choose tasks or activities that have a quick payoff, rather than those that take more effort, but provide bigger, delayed rewards, thus they may struggle with school and other activities in which they are expected to be more self-reliant (NIMH, 2008).
Although hyperactivity tends to decrease as a child ages, teens who continue to be hyperactive may feel restless and try to do too many things at once. Furthermore, daily tasks such as getting up in the morning, preparing to leave the house for work, arriving at work on time, and being productive on the job can be especially challenging for adults with ADHD (NIMH, 2008). The most common and frequently prescribed psychotropic drugs for ADHD are stimulant medications. Between 1987 and 1996, the overall annual rate of prescription stimulant medication use by children and adolescents increased over 250%, from 1.4 per 100 persons to 3.9 per 100 persons (Meaux et al., 2006). Results from double-blind, placebo controlled studies have consistently demonstrated that stimulants are superior to placebo in decreasing hyperactivity and impulsivity and increasing attention in individuals with ADHD (Brown & Rosa, 2002).
Adderall is a short-acting dextroamphetamine. The delivery of Adderall-XR is unique because it allows for delivery over the course of 12 hr (Brown & Rosa, 2002). Mixed amphetamine salts extended release (MAS XR)-Adderall XR- is a once-daily, single-entity amphetamine approved by the US Food and Drug Administration for the management of ADHD in children aged 6 to 12 years and in adults (Spencer et al., 2006). The effects of the stimulants are exemplified through the sustained attention, impulsivity, and over activity. There is evidence suggesting that the stimulants can enhance academic productivity and performance, decrease aggressive behaviors in the short-term, and improve social skills, peer relationships, and even mother-child interactions (Brown & Rosa, 2002).
Although evidence supporting stimulants for ADHD appear impressive there are short-term adverse effects that include: insomnia, anorexia, nausea, abdominal pain, headaches, lability of mood, anxiety, nightmares, weepiness, tachycardia, and blood pressure changes (Brown & Rosa, 2002). The long-term effects typically include the possibility of weight loss or stunting growth, adverse cardiovascular effects, and drug dependence or abuse (Brown & Rosa, 2002).
Much of the current research has been done with younger children, thus Spencer et al. (2006) assessed the efficacy and safety of Adderall XR for adolescents in a 4-week, randomized, multicenter, double-blind, placebo controlled, parallel-group, forced-dose-titration study. The study included 258 adolescents aged 13 to 17 years. Adolescents were randomly placed into 1 of 4 active treatments (MAS XR 10, 20, 30, or 40 rag/d) or to placebo (Spencer et al., 2006). This study used a forced-dose-titration design in which patients randomized to the 10-mg/d group received 1 dose of 10 mg/d for 4 weeks. Patients randomized to the 20-mg/d group received 1 dose of 10 mg/d for the first week and 1 dose of 20 mg/d for the remaining weeks; patients randomized to the 30-mg/d group received 1 dose of 10 mg/d for the first week, 1 dose of 20 mg/d for the second week, and 1 dose of 30 mg/d for the remaining 2 weeks; and patients randomized to the 40-mg/d group received 1 dose of 10 mg/d for the first week, 1 dose of 20 mg/d for the second week, 1 dose of 30 mg/d for the third week, and 1 dose of 40 mg/d for the fourth week (Spencer et al., 2006). The primary efficacy measure was change from baseline to end point in the ADHD Rating Scale-IV score, an 18 item scale reflecting the presence of ADHD. The secondary efficacy measure was the score on the Clinical Global Impressions-Improvement (CGI-I) scale for ADHD. Safety was assessed by recording adverse events, vital signs, and body weight at all study visits and 30 days after drug discontinuation (Spencer et al., 2006).
To detect an effect size of 0.78 on the ADHD-RS-IV scale between one MAS XR group and the placebo group at >95% power and an c~ level of 0.05 (2-tailed) using a 2-sample t test, it was necessary to randomize-45 patients to each of the 5 treatment groups (Spencer et al., 2006). The primary efficacy analysis was conducted on the change from baseline to end point of ADHD-RS-IV populations using a 2-way analysis of covariance (ANCOVA) model. Each dose of study drug was compared with placebo using the ANCOVA model at the 0.05 level by including treatment (MAS XR 10, 20, 30, and 40 mg/d, and placebo), site, and the baseline score (covariate) (Spencer et al., 2006). Significant statistical improvement was found in the total scores on the ADHD-RS-IV for adolescents in the MAS XR treatment groups beginning during the first treatment week and continuing throughout the 4-week study (Spencer et al., 2006). A dose-dependent increase in the incidence of anorexia was observed when analyzing the safety of MAS XR (Spencer et al., 2006). For efficacy the null hypothesis was rejected. A significant main effect was exemplified. For safety, the study exemplified similar results to other studies in younger populations. The most frequently reported adverse effects were mild or moderate, and changes in vital signs were not clinically significant (Spencer et al., 2006).
There appears to be a limited number of confounds in this study. Dr. Spencer and his team took careful steps to assure the adolescents were similar in diagnosis, weight, and IQ. He does recognize the limitations of the study for the weight limit and suggests further studies be done to further understand the adverse effects for adoescents less than 75kg. However, the studied was funded by Shire Pharmaceuticals, which is the drug company that produces Adderall XR. Dr. Spencer along with Dr. Wilens and Dr. Beiderman receive support and funding from pharmaceutical companies that produce Adderall and Adderall XR. It would be desirable to have this studied repeated by an outside source to determine the efficacy of this study. It would also be desirable to test the medications over a longer period of time to determine the long term effects of the drug. While it appears that the research about efficacy and safety have strong internal validity, it may be limited to the amount of time the study took (4 weeks) to complete. It would be hard to determine short term and long term effects of the 40mg dose especially due to the adolescents only receiving this dose for one week. This study does not take into account any long term safety effects of any level of dosage. The internal validity of this study appears to be sound, the external validity for adolescent ADHD populations over time is yet to be determined.
Brown, R., and Rosa, A. (2002). Recent developments in the pharmacotherapy of attention-deficit/hyperactivity disorder (ADHD). Professional Psychology: Research and Practice. 33(6), 591-595. doi:10.1037/0735-7028.33.6.591.
Meaux, J., Hester, C., Smith, B., & Shoptaw, A. (2006). Stimulant medications: A trade-off? the Lived experience of adolescents with ADHD. Journal for Specialists in Pediatric Nursing, 11(4), 214-226. doi:10.1111/j.1744-6155.2006.00063.x.
National Institute of Mental Health. (2008). Attention Deficit Hyperactivity Disorder. National Institutes of Health. 08-3572. <NIMH.nih.gov>
Spencer, T., Wilens, T., Biederman, J., Weisler, R., Read, S., Pratt, R., (2006) Efficacy and safety of mixed amphetamine salts extended release (adderall XR) in the management of attention-deficit/hyperactivity disorder in adolescent patients: A 4-week, randomized, double-blind, placebo-controlled, parallel-group study. Clinical Therapeutics, 28(2): 266-279