Spencer TJ, Wilens TE, Biederman J, Weisler RH, Read SC, Pratt R. 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
The ability to recognize and diagnose attention-deficit/hyperactivity disorder (ADHD) has increased in recent years. The persistence of ADHD symptoms puts adolescents with ADHD at risk for long-term adverse psychosocial outcomes.
The primary goal of this study was to assess the efficacy and safety of mixed amphetamine salts extended release (MAS XR) in the management of adolescents with ADHD.
This was a 4-week, randomized, multicenter, double-blind, placebo-controlled, parallel-group, forced-dose-titration study. Adolescents aged 13 to 17 years with ADHD were randomized to 1 of 4 active treatments (MAS XR 10, 20, 30 or 40 mg/d) or to placebo. All doses were given in the morning. 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. The primary efficacy measure was change from baseline to end point in the ADHD Rating Scale-IV (ADHD-RS-IV) score. The secondary efficacy measure was the score on the Clinical Global Impressions-Improvement (CGI-I) scale for ADHD. ADHD-RS-IV total scores were analyzed post hoc in patients with low baseline ADHD-RS-IV severity (ie, patients with baseline ADHD-RS-IV total scores less than the median) and high baseline ADHD-RS-IV severity (ie, patients with baseline ADHD-RS-IV total scores greater than the median). Safety was assessed by recording adverse events, vital signs, and body weight at all study visits and 30 days after drug discontinuation.
Of the 287 randomized adolescents, 258 completed the study. The intent-to-treat (ITT) population included 278 patients. The majority of patients were male (65.5%) and white (73.7%) The mean weight (57.8 kg [127.1 lb]) at baseline and the mean height (163.8 cm [64.5 in]) at screening were comparable across all MAS XR treatment groups. Patients in the placebo group had a mean weight of 59.8 kg (131.6 lb) and a mean height of 166.1 cm (65.4 in). Most (56.5%) of the patients had ADHD combined inattentive/hyperactive-impulsive subtype. Two hundred nineteen (78.8%) patients were treatment naive, and 59 (21.2%) had received treatment for ADHD within 30 days before screening. ITT analysis of the ADHD-RS-IV revealed statistically significant (P < 0.001) improvement in mean ADHD-RS-IV total scores in all 4 MAS XR treatment groups, compared with placebo, at all weeks throughout the 4-week study; the mean change from baseline to end point was -17.8 in the MAS XR 10- to 40-mg/d groups and -9.4 in the placebo group. Significant treatment effects were observed in both the ADHD-RS-IV inattentive (P < 0.001) and hyperactive-impulsive (P < 0.001) subscales from baseline. In patients with low baseline ADHD-RS-IV severity, statistically significantly (P < or = 0.01) greater improvements were observed in the MAS XR 20-, 30-, and 40-mg/d groups than in the placebo group; in patients with high baseline ADHD-RS-IV severity, statistically significantly (P < or = 0.02) greater improvements were observed in all active treatment groups compared with placebo. On the CGI-I scale at end point, a higher percentage of adolescents in all MAS XR treatment groups were considered improved (MAS XR 10 mg/d, 51.9% [P < 0.01]; 20 mg/d, 66.0% [P < 0.001]; 30 mg/d, 70.7% [P < 0.001]; 40 mg/d, 63.9% [P < 0.001]) compared with adolescents receiving placebo (26.9%). The most common adverse events in patients receiving MAS XR versus placebo were anorexia/decreased appetite (35.6% vs 1.9%), headache (16.3% vs 22.2%), insomnia (12.0% vs 3.7%), abdominal pain (10.7% vs 1.9%), and weight loss (9.4% vs 0%). Most adverse events were mild or moderate in intensity (97.5%); no serious adverse events were reported.
The adolescents with ADHD treated with 10- to 40-mg/d MAS XR up to 4 weeks had significant improvements in ADHD symptoms compared with those who received placebo. Results of this study suggest that once-daily dosing with MAS XR up to 40 mg was effective and well tolerated for the management of ADHD in these adolescents.
"Importantly, long-acting formulations lead to greater medication compliance in teenagers compared to rapid-acting stimulants (Sanchez, Crismon, Barner, Bettinger, & Wilson, 2005). Effect sizes for ADHD symptom reduction in recent trials of OROS-MPH (e.g., Wilens et al., 2006) as well as other once-daily ADHD medications (e.g., Spencer et al., 2006) are in the medium-to-large range among teens, consistent with meta-analytic findings for immediate-release stimulants (Smith et al., 2000). Altogether, the best available evidence indicates that stimulants have significant benefits in multiple domains of functioning for adolescents. "
[Show abstract][Hide abstract] ABSTRACT: Attention-Deficit/Hyperactivity Disorder (ADHD) is highly prevalent among adolescents enrolled in behavioral health services but remains undertreated in this age group. Also the first-line treatment for adolescent ADHD, stimulant medication, is underutilized in routine practice. This article briefly describes three behavioral interventions designed to promote stronger integration of medication interventions into treatment planning for adolescent ADHD: family ADHD psychoeducation, family-based medication decision-making, and behavior therapist leadership in coordinating medication integration. It then introduces the Medication Integration Protocol (MIP), which incorporates all three interventions into a five-task protocol: ADHD Assessment and Medication Consult; ADHD Psychoeducation and Client Acceptance; ADHD Symptoms and Family Relations; ADHD Medication and Family Decision-Making; and Medication Management and Integration Planning. The article concludes by highlighting what behavior therapists should know about best practices for medication integration across diverse settings and populations: integrating medication interventions into primary care, managing medication priorities and polypharmacy issues for adolescents with multiple diagnoses, providing ADHD medications to adolescent substance users, and the compatibility of MIP intervention strategies with everyday practice conditions.
"We identified 422 abstracts of which 148 met selection criteria . Of these, 47 (Ahmann et al., 1993, 2001; Arnold et al., 2004; Barkley, McMurray, Edelbrock, & Robbins, 1990; Biederman, Boellner, et al., 2007; Biederman et al., 2002, 2008; Biederman, Krishnan, Zhang, McGough, & Findling, 2007; Chacko et al., 2005; Daviss et al., 2008; Findling et al., 2008; Fine & Johnston, 1993; Firestone, Musten, Pisterman, Mercer, & Bennett, 1998; Gau, Shen, Soong, & Gau, 2006; Gillberg et al., 1997; Greenhill et al., 2006; Greenhill, Findling, & Swanson, 2002; Grizenko, Shayan, Polotskaia, Ter-Stepanian, & Joober, 2008; Hinshaw, Buhrmester, & Heller, 1989; James et al., 2001; Kelsey et al., 2004; Klorman, Brumaghim, Fitzpatrick, Borgstedt , & Strauss, 1994; Kratochvil et al., 2007; Manos, Short, & Findling, 1999; Matza et al., 2004; Mayes, Crites, Bixler, Humphrey, & Mattison, 1994; McCracken et al., 2003; McGough et al., 2005; Michelson et al., 2002; Newcorn et al., 2008; Newcorn, Spencer, Biederman, Milton, & Michelson, 2005; Pelham, Aronoff, et al., 1999; Pelham et al., 1990; Pelham, Burrows-Maclean, et al., 2005; Pelham, Manos, et al., 2005; Pelham, Gnagy, et al., 1999; Pliszka, Browne, Olvera, & Wynne, 2000; Rapport, Randall, & Moffitt, 2002; Schachar, Tannock, Cunningham , & Corkum, 1997; Short, Manos, Findling, & Schubel, 2004; Silva et al., 2006; Smithee, Klorman, Brumaghim, & Borgstedt, 1998; Spencer et al., 2006; Swanson et al., 2004; Whalen et al., 1989; Wigal, et al., 2004, 2006) reported EE in some manner and eight studies (Biederman, Boellner, et al., 2007; Daviss et al., 2008; Manos et al., 1999; Newcorn et al., 2008; Pelham, Aronoff, et al., 1999; Pelham et al., 1990; Pelham, Gnagy, et al., 1999; Pliszka et al., 2000) had two active investigational treatment arms; 55 data sets reported evidence of EE associated with medication for the treatment of ADHD. For patients receiving active drug, 42 data sets reported EE as a percentage, 11 data sets reported EE as a mean score based on a prespecified rating scale, and 2 data sets reported EE occurred, but they did not report a rate. "
"A number of randomized controlled clinical trials have shown that controlled-release MAS (MAS-CR) is effective versus placebo for reducing ADHD symptoms in children, adolescents, and adults (Table 3) (Biederman et al. 2002; Spencer et al. 2006b; Weisler et al. 2006). An analog classroom trial in children showed that a significant effect of MAS-CR over placebo emerged at 1.5 h post-dosing and was maintained for up to 12 h, based on improvements from baseline at end point in SKAMP-D and math test scores (McCracken et al. 2003). "
[Show abstract][Hide abstract] ABSTRACT: Individuals with attention-deficit/hyperactivity disorder (ADHD) show pervasive impairments across family, peer, and school or work functioning that may extend throughout the day. Psychostimulants are highly effective medications for the treatment of ADHD, and the development of long-acting stimulant formulations has greatly expanded the treatment options for individuals with ADHD. Strategies for the formulation of long-acting stimulants include the combination of immediate-release and delayed-release beads, and an osmotic-release oral system. A recent development is the availability of the first prodrug stimulant, lisdexamfetamine dimesylate (LDX). LDX itself is inactive but is cleaved enzymatically, primarily in the bloodstream, to release d-amphetamine (d-AMP). Several clinical trials have demonstrated that long-acting stimulants are effective in reducing ADHD symptoms compared with placebo. Analog classroom and simulated adult workplace environment studies have shown that long-acting stimulants produce symptom reduction for at least 12 h. Long-acting stimulants exhibit similar tolerability and safety profiles to short-acting equivalents. While variations in gastric pH and motility can alter the availability and absorption of stimulants released from long-acting formulations, the systemic exposure to d-AMP following LDX administration is unlikely to be affected by gastrointestinal conditions. Long-acting formulations may also improve adherence and lower abuse potential compared with their short-acting counterparts. The development of long-acting stimulants provides physicians with an increased range of medication options to help tailor treatment for individuals with ADHD.
ADHD Attention Deficit and Hyperactivity Disorders 04/2013; 5(3). DOI:10.1007/s12402-013-0106-x
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