New Research on Pharmacologic Therapy in ADHD  CME Norra MacReady   David W. Goodman, MD

Pharmacologic research presented in posters at the 2008 US Psychiatric and Mental Health Congress reflected an increasingly sophisticated understanding of attention-deficit/hyperactivity disorder (ADHD) and the ways in which patients respond to treatment. Adult ADHD Relatively little is known about the demographics of adults with ADHD, according to Craig B. H. Surman, MD, of the Massachusetts General Hospital and Harvard Medical School. In his poster, he presented the results of a random telephone survey of 6000 adults from around the country. Of those people, 354 (5.9%) had been diagnosed with ADHD at some time in their lives. Many of those patients who had been diagnosed with ADHD also had received diagnoses of depression (52.5%), anxiety (48%), bipolar disorder (31.1%), or obsessive-compulsive disorder (27.1%). Compared with people without ADHD, those with the disorder were significantly more likely to be male, young (18-24 years old), have a high school degree or less, have an annual family income of less than $25,000, and be single or never married. Most of these individuals had received their diagnoses in childhood, but the vast majority -- 75% -- were not currently taking medication. Of the adults who had never been diagnosed with ADHD, 2.8% to 11.3% met the diagnostic criteria when they were evaluated during the survey with various standard screening questionnaires.[1] Stimulant medications are the cornerstone of pharmacologic ADHD treatment for adults as well as children, but there is mixed evidence that they may elicit or exacerbate comorbid anxiety.[2-6] In a randomized, double-blind, placebo-controlled trial of adults with ADHD and comorbid social anxiety disorder, conducted by lead author Todd Durell, MD, of Lilly Research Laboratories in Indianapolis, and colleagues, atomoxetine in a dose of 40-100 mg/day for 18 weeks was associated with a statistically significant and clinically meaningful decrease in symptoms of anxiety, as well as ADHD.[7] Patients vary widely in their response to various doses of psychostimulants. In a small, open-label study of adults with ADHD, lisdexamfetamine (LDX) appeared to overcome this problem. The subjects started with 50 mg of LDX and received escalating doses in 50-mg increments in 96-hour intervals, up to 250 mg. After ingestion, LDX is cleaved into l-lysine and the active compound, d-amphetamine. In this study, plasma d-amphetamine levels increased linearly with the dose, with low inter- and intra-subject variability in pharmacokinetic parameters with an overall variability in maximum observed plasma concentration of 26.9% at all doses and 19.8% for 50-150 mg LDX. Of 20 patients initially enrolled, 10 discontinued before reaching the maximum dose when they met predetermined blood pressure cutoff criteria and 1 withdrew, according to the researchers, led by James Ermer, MS, of Shire Development, Inc. (Wayne, Pennsylvania). The analysis included all patients participating at each dose level. "There were no clinically remarkable findings in ECG, or laboratory studies."[8] In 2 other posters, lead author Richard Weisler, MD, of Duke University Medical Center, and colleagues presented findings on the safety and efficacy of LDX in 349 patients. The patients were first enrolled in a 4-week randomized, double-blind trial in which they received either a placebo or LDX in doses of 30, 50, or 70 mg/day. All doses of LDX were associated with significant symptom improvement compared to placebo (P < .0001). LDX also was associated with small but statistically significant elevations in heart rate (the least squares mean [95% confidence interval] change from baseline in pulse in the placebo/30 mg/50 mg/and 70 mg groups were 0.0 [-2.2, 2.2]; 2.8 [1.2, 4.4]; 4.2 [2.6, 5.9]; and 5.2 [3.6, 6.8] beats per minute, respectively), although there were no significant changes in blood pressure. Other adverse events (AEs) were similar to those previously reported for LDX and other long-acting stimulants. The authors examined the long-term effects of LDX in the same patient population, with those previously in the placebo group receiving LDX starting in a dose of 30 mg/day. In this study, which was open-label, the patients were exposed to LDX for a mean of 266.4 days. A total of 191 completed the trial. The treatment was well-tolerated and produced sustained improvement in ADHD symptoms. Most of the AEs were mild to moderate, with few clinically relevant effects on cardiovascular parameters, although a small but statistically significant increase in blood pressure and heart rate was noted for all groups at endpoint. Pulse rate increased from 74.6 beats per minute (bpm) at baseline to 76.9 bpm at endpoint in the population that had previously taken LDX, and from 71.0 to 78.6 bpm in the LDX-naive population; pulse rate also increased from 74.1 to 77.1 bpm in the placebo population. Blood pressure increased from 117.6 (9.8)/75.4 (8.0) mm Hg at baseline in the prior LDX population, and from 115.4 (11.0)/75.3 (8.2) to 119.5 (13.7)/76.7 (8.4) mm Hg in the LDX-naive population. In the control population, blood pressure changed from 117.3 (10.)/75.4 (8.0) to 120.5 (11.7)/76.8 (8.2) mm Hg. The authors concluded LDX was safe and effective in the long-term management of ADHD.[9,10] Patients using a controlled-release form of methylphenidate (OROS-MPH) may benefit from individualized dosing, according to 1 study. Researchers evaluated the agent in 226 adult patients and started with a dose of 36 mg/day, which was increased in 18-mg increments every 7 days until the patients either reached a protocol-defined clinical response, or achieved the maximum dose of 108 mg/day. The mean final dose was 67.7 mg/day. Some patients responded at each dose level, but optimal responses required individualized dosing. Doses ranging from 54 to 108 mg/day were associated with more robust improvement than the lower doses. OROS-MPH was safe and well-tolerated, wrote the authors, led by H. Lynn Starr, MD, of Ortho-McNeil Janssen Scientific Affairs (Titusville, New Jersey).[11] Further evidence that people with ADHD would benefit from a longer-acting stimulant came in a survey of 402 physicians who regularly treat adult or pediatric patients. They reported that 66% of their patients experienced a significant decline in symptom control before 5 PM. One in 5 patients took their once-daily medication twice a day or more. While lack of efficacy was the most common reason for changing medication (39%), poor duration accounted for 35%, lead author Gisberg wrote. Thirty percent of patients had been prescribed a new once-daily medication in the past 6 months.[12] Pediatric Studies Several studies assessed the safety and efficacy of guanfacine extended-release (GXR), which is expected to receive US Food and Drug Administration approval early in 2009, for ADHD patients ranging in age from 6 to 17 years. In 1 study, lead author Lee Boyle, PhD, of Shire Development, Inc., and colleagues assessed the effect of somnolence, fatigue, and sedation -- the most common AEs associated with guanfacine -- on cognitive function. They studied 178 patients who were randomized to GXR or a placebo for 6.5 weeks. More children in the GXR group were rated "significantly improved" by the study's endpoint than subjects on placebo, with no impairment of cognitive function. GXR also appeared to reduce sleepiness and increase alertness. The authors concluded that cognitive function is not diminished by any somnolence, sedation, or fatigue that may occur with GXR.[13] In a separate study,[14] Stephen J. Glatt, PhD, of the State University of New York Upstate Medical University, and colleagues observed that the sedative effects associated with GXR wane over time. Data pooled from 3 studies of 813 children and adolescents with ADHD showed a significant inverse correlation between treatment duration and the incidence of sedation AEs. They suggested that the risk for sedation decreases as patients acclimate to GXR.[14] In a study of combination therapy, Lawrence D. Ginsberg, MD, of Red Oak Psychiatry Associates in Houston, Texas, and colleagues examined the effect of adding open-label GXR to a regimen already consisting of methylphenidate (MPH) or amphetamine. The subjects, 75 patients with a mean age of 11 years, stayed on combination therapy for 9 weeks, with GXR doses ranging from 1 to 4 mg/day. Ninety-two percent of the patients experienced some type of AE, most commonly upper abdominal pain, fatigue, irritability, and somnolence. Five patients discontinued the study because of AEs. However, no abnormalities in cardiac function were observed, and most of the AEs were mild to moderate. The addition of GXR was associated with a significant reduction in ADHD symptoms over that achieved with the stimulants alone (P < .0001). However, the authors warned against drawing firm conclusions yet, given the open-label nature of the study and the lack of a placebo group.[15] MPH is a well-established treatment for ADHD, but many experts are concerned about its potential for cardiovascular AEs. Frank López, MD, of the Children's Developmental Center in Winter Park, Florida, and coauthors reported few clinically significant cardiovascular changes in an open-label study of 324 children aged 6 to 12 years who used the methylphenidate transdermal system (MTS) for 12 months. The patients wore the patches on alternating hips for 9 hours a day, in doses ranging from 10 to 30 mg. Some patients experienced moderate, variable increases in pulse and blood pressure, but there were no clinically important trends in ECG readings and no serious, drug-related cardiovascular events.[16] Most patients wear the MTS on the hip, but its efficacy when applied elsewhere on the body has not been adequately studied. Mario González, PhD, of P Kinetics, International (Pembroke Pines, Florida), and colleagues compared the pharmacokinetics of hip and scapula placement. A total of 27 children with a mean age of 9.6 years participated in this open-label trial, in which they were randomized to wear the patch on 1 site for 16 hours and then switched locations after a washout period of at least 7 days. Twenty-three patients completed the study. Hip application was associated with higher plasma concentrations of MPH, with approximately 30% greater bioavailability. Erythema and discomfort were the most common AEs, with more severe erythema associated with the hip patch and slightly more discomfort reported with the scapula patch. However, both effects were mild. The authors concluded that patch site does influence drug bioavailability.[17]