Randomized, 6-Week, Placebo-Controlled Study of Treatment for Adult Attention-Deficit/Hyperactivity Disorder: Individualized Dosing of Osmotic-Release Oral System (OROS) Methylphenidate With a Goal of Symptom Remission.

OBJECTIVE: To evaluate the efficacy and safety of individualized dosing within the approved dose range for osmotic-release oral system (OROS) methylphenidate hydrochloride in adults with attention-deficit/hyperactivity disorder (ADHD). METHODS: A double-blind, 6-week trial was conducted between July 2009 and February 2010 at 35 US sites. Adults with ADHD (DSM-IV diagnostic criteria) and a screening ADHD Investigator Symptom Rating Scale (AISRS) score > 24 were randomly assigned to OROS methylphenidate 18 mg or matching placebo. Treatment dose could be increased at 18 mg increments, up to 72 mg/d, until an optimal dose was achieved. AISRS score changes from baseline to end point (primary outcome) were analyzed using analysis of covariance. RESULTS: At baseline, the intent-to-treat population of 169 OROS methylphenidate and 172 placebo subjects (mean age = 35.8 years) had mean (standard deviation [SD]) AISRS scores of 37.8 (6.94) and 37.0 (7.51), respectively. OROS methylphenidate-treated subjects exhibited a significantly greater mean (SD) AISRS score improvement than placebo subjects (-17.1 [12.44] vs -11.7 [13.30]; P < .001). In general, OROS methylphenidate-treated subjects experienced greater improvements than placebo subjects in secondary measures of symptom frequency, cognitive function, work productivity, and quality-of-life. Little effect of OROS methylphenidate was observed in exploratory sleep assessments. The adverse event pattern was similar to previous reports of stimulants in adults with ADHD. CONCLUSIONS: OROS methylphenidate treatment with individualized doses titrated to achieve symptom remission demonstrated greater ADHD symptom reduction than placebo treatment. These data support the overall efficacy of OROS methylphenidate treatment in the management of adults with ADHD and provide new possibilities for additional intervention. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00937040.

Efficacy, safety, and impact on hospitalizations of paliperidone palmitate in recent-onset schizophrenia.

OBJECTIVE: To evaluate the efficacy, safety, and impact on hospitalizations of long-acting injectable paliperidone palmitate (PP) treatment, in patients with recent-onset schizophrenia who had not responded satisfactorily to oral antipsychotics. METHODS: In this 18-month, open-label, Phase-IIIb study from Asia-Pacific region, patients (18-50 years) with recent-onset (≤5 years) schizophrenia unsatisfactorily treated with previous oral antipsychotics were initiated on PP 150 mg eq on day 1, 100 mg eq on day 8, followed by flexible once monthly maintenance doses of 50-150 mg eq. The number and duration of hospitalizations were compared using a mirror analysis method between two periods: retrospective (12 months before PP initiation) and prospective (12 and 18 months after PP treatment) periods. RESULTS: A total of 303 out of 521 (58%) patients (mean age, 28.7 years; 65.5% men, 92.5% Asian) completed the study. Positive and Negative Syndrome Scale (PANSS) total score improved significantly from baseline to month 18 (mean [standard deviation, SD] change: -11.3 [21.38], P<0.0001, primary endpoint). Subgroup analysis revealed greater improvements among patients with worse disease severity at baseline: PANSS ≥70 versus <70 (mean [SD] change: -23.1 [24.62] vs -4.7 [15.98], P<0.0001 each). Secondary efficacy endpoints such as Clinical Global Impression of Schizophrenia (CGI-SCH), Medication Satisfaction Questionnaire (MSQ) scores showed significant improvements (P<0.0001) from baseline; 33.3% patients achieved symptom remission. In mirror analyses set (N=474), PP significantly (P<0.0001) reduced mean number of hospitalization days/person/year (12-month: 74.3 vs 19.7; 18-month: 74.3 vs 18.9) as well as percentage of patients requiring hospitalization in past 12 months (12-month: 39.7% vs 24.6%; 18-month: 39.7% vs 25%), and PP treatment increased the proportion of patients not requiring hospitalization (12-month: 60.3% vs 75.4%; 18-month: 60.3% vs 75%) from retrospective to prospective period. Adverse events (≥15%) were extrapyramidal symptoms-related (31.3%), injection-site pain (18.6%), and insomnia (15.2%). CONCLUSION: PP was efficacious and generally tolerable with significant reductions observed in both number of hospitalizations and days spent in hospital.

Topiramate monotherapy use in women with and without epilepsy: pregnancy and neonatal outcomes.

PURPOSE: To evaluate fetal or neonatal outcomes (with a focus on major congenital anomalies) with use of topiramate monotherapy and to examine whether differences occurred in the reporting and patterns of these outcomes for pregnant women with and without epilepsy. METHODS: Spontaneous, postmarketing reports involving women who used topiramate monotherapy during pregnancy from 18 July 1995 (International Birth Date of topiramate) through 30 April 2011 were retrieved from the sponsor's (Janssen Research & Development, LLC) Global Medical Safety database. All formulations for topiramate, used as monotherapy, were selected for the analysis. Monotherapy was defined as any situation where no other AED was listed in the pregnancy case report, either as a suspect or concomitant medication, regardless of indication. Results were summarized descriptively. RESULTS: A total of 1163 cases of women who used topiramate monotherapy during pregnancy (for any indication) were retrieved from the Global Medical Safety database. Since some women used topiramate for more than one indication, there were a total of 1199 reported indications for topiramate monotherapy, which were primarily for treatment of epilepsy (n=599), accounting for half of the indications, and migraine prophylaxis (n=240, 20.0%). Out of 1163 cases, pregnancy outcome was reported in 50.6% (n=589). Live birth was the most frequently reported outcome, regardless of indication (epilepsy, 78.8% [312/396]; prophylaxis of migraine, 59. 3% [48/81]; other indication, 64.4% [85/132]). Cleft lip or palate anomalies (epilepsy, n=15; migraine, n=2; other indication, n=4; and indication not reported, n=2), limb, hand, or other skeletal anomalies (epilepsy, n=13; migraine, n=2; other indication, n=0; and indication not reported, n=1), and respiratory or cardiovascular anomalies (epilepsy, n=12; migraine, n=1; other indication, n=1; and indication not reported, n=2) were the most often reported major fetal or neonatal anomalies. More reported major fetal or neonatal anomalies occurred in patients being treated for epilepsy (53/79 anomaly-indication pairs) compared with patients being treated for migraine prophylaxis (10/79 anomaly-indication pairs). CONCLUSION: Although incidence rates cannot be calculated based on spontaneous adverse event reporting, this summary of reported pregnancy and neonatal outcomes with use of topiramate monotherapy suggests that the risk for major fetal or neonatal anomalies may differ based on the indication for topiramate.

Methylphenidate in children with ADHD with or without learning disability.

OBJECTIVE: To explore treatment response to Osmotic Release Oral System(®) (OROS) methylphenidate in children with ADHD with and without comorbid learning disability (LD). METHOD: Data were analyzed from two 6-week, double-blind, randomized, placebo-controlled, crossover studies evaluating individually determined doses of OROS methylphenidate versus placebo in 135 children (ages 9 to 12 years) with ADHD with or without an LD in reading, math, or both. The sample was demographically diverse, with 31% females and more than 40% minority, predominantly African American and Hispanic. On two laboratory school days, participants received either OROS methylphenidate or placebo and were given a battery of cognitive and behavioral tests. RESULTS: Treatment with OROS methylphenidate led to improvement in ADHD Rating Scale scores for participants with or without comorbid LD. Both groups performed better during treatment with OROS methylphenidate than placebo on measures of cognitive skills (i.e., Test of Variables of Attention, Finger Windows Backwards), academically related tasks (i.e., Dynamic Indicators of Basic Early Literacy Skills, Test of Handwriting Skills-Revised, Permanent Product Math Test), and observed classroom behavior (i.e., Swanson, Kotkin, Alger, M-Flynn, and Pelham Scale). CONCLUSION: In children with ADHD with or without comorbid LD, behavior and performance improved during treatment with OROS methylphenidate.

Time course of treatment effect of OROS® methylphenidate in children with ADHD.

OBJECTIVE: The authors evaluated the time course of the treatment effect of Osmotic-Release Oral System methylphenidate (OROS(®) MPH) HCl (Concerta(®), Raritan, NJ) CII in children with ADHD. METHOD: Data were combined from two double-blind, randomized, placebo-controlled, cross-over, analog classroom studies in children (9-12 years) with ADHD. Participants received an individualized dose of placebo or OROS(®) MPH on two laboratory school days. Permanent Product Math Test and Swanson, Kotkin, Agler, M-Flynn, and Pelham scores were evaluated 0.5 hr before dosing and 1, 2, 4, 10, 11, and 12.5 hr post dose. Analysis used a repeated-measures mixed model. RESULTS: Treatment effects were present at all postdose assessment points (p < .0001 for all comparisons, n = 139). Adverse events were similar to previous reports for OROS(®) MPH. CONCLUSION: A robust treatment effect occurred with OROS(®) MPH; onset was at 1 hr and persisted for at least 12.5 hr after dosing.

Carisbamate in essential tremor: brief report of a proof of concept study.

The efficacy and safety of carisbamate, an investigational neuromodulator currently in development for epilepsy, were examined in a multicenter, randomized, double-blind, cross-over, placebo-controlled study of essential tremor. Sixty-two patients (intent-to-treat analysis set; mean age 64 years; 66% men) received carisbamate 400 mg/day or matching placebo in a crossover study design with two 21-day treatment periods. The Fahn-Tolosa-Marín Tremor Rating Scale (TRS) was the primary assessment tool. Carisbamate and placebo treatment did not differ in their effect on the TRS (P = 0.94) or on measures of affect, mood, or quality of life. Carisbamate was generally well tolerated and had an adverse event profile comparable to that of placebo.

Effects of galantamine versus donepezil on sleep in patients with mild to moderate Alzheimer disease and their caregivers: a double-blind, head-to-head, randomized pilot study.

OBJECTIVE: To examine the effects of galantamine and donepezil on patient and caregiver sleep. METHODS: In this randomized, 8-week, double-blind, parallel-group, multicenter, pilot comparison of galantamine and donepezil, safety and efficacy data were collected. Objective and subjective changes in sleep of patients (N = 63) and their caregivers were measured. Clinicians assessed changes in patient global function. As this was a pilot study, only descriptive statistics are presented. RESULTS: In general, neither galantamine nor donepezil, at stable doses, were associated with decrements in actigraphy sleep measurements. However, mean scores in all measures of sleep showed a tendency for minimal improvements in galantamine-treated patients and minimal decrements in the donepezil-treated patients. The same tendencies were present in caregiver sleep measures. Global function either improved or remained stable in a higher percentage of patients treated with galantamine than with donepezil. Galantamine and donepezil were both well tolerated and safe. CONCLUSIONS: This pilot study was the first to compare the effects of these drugs on sleep in patients or caregivers. Both drugs were safe and well tolerated. Neither galantamine nor donepezil negatively affected sleep; however, on every measure, there were suggestions of slightly more benefit associated with galantamine treatment. Although these results are suggestive of a differential effect of the drugs on sleep, further research is needed to confirm the clinical significance.

Undertreatment of patients with Alzheimer's disease in an elderly United States population.

BACKGROUND: The aim of this study was to assess the undertreatment of elderly mild to moderate Alzheimer's disease (AD) patients in the United States utilizing baseline data from a community-based trial that has established comparability to national survey samples on demographic characteristics. METHODS: Baseline data were used from an open-label, 12-week, postapproval study of compliance with galantamine, an AChEI and nicotinic receptor modulator, and vitamin E. A total of 2,114 patients from 406 community-based US practices in which physicians had previously treated patients with acetylcholinesterase inhibitors (AChEIs) were included in the study. This population reflects a large, ethnically diverse patient pool consistent with the demographics of the elderly population in the United States, atypical of those enrolled in most AD trials. RESULTS: The majority of patients (64.5%) were described by either themselves or their caregivers as not having received prior AChEI treatment. Positive associations were found between past AChEI treatment and longer time since diagnosis, white race, higher education, medical care by a neurologist, and older caregivers. The likelihood of having received previous AChEI treatment was higher among white patients (61.9%) than among those from other ethnic groups combined (25.8%). CONCLUSIONS: The similarity of patient demographic characteristics to the 2000 US Census figures for the population aged >65 years makes this data set a potentially powerful tool for planning public health initiatives. Findings suggest that patients with mild to moderate AD are undertreated and that specialist and nonspecialist organizations should discuss and implement ways to optimize management of this disease.