Explore the vast range of titles available.

Abstract Background and Hypothesis The dopamine theory of schizophrenia suggests that antipsychotics alleviate symptoms by blocking dopamine D2/3 receptors, yet a significant subset of patients does not respond adequately to treatment. To investigate potential predictors, we evaluated d-amphetamine-induced dopamine release and 1-year clinical outcomes in 21 antipsychotic-naive patients with first-episode schizophrenia. Study Design Twenty-one antipsychotic-naive patients (6 female) underwent dopamine D2/3 receptor radioligand [11C]-(+)-PHNO positron emission tomography. For estimating dopamine release, scans were performed with and without d-amphetamine pretreatment. The Positive and Negative Syndrome Scale was performed at regular intervals over 1 year while receiving treatment in a naturalistic setting (Clinical Trial Registry: EUDRACT 2010-019586-29). Study Results A group analysis revealed no significant differences in d-amphetamine-induced dopamine release between patients with or without clinically significant improvement. However, d-amphetamine-induced dopamine release in ventral striatum was significantly associated with reductions in positive symptoms (r = 0.54, P = .04; uncorrected P-values); release in globus pallidus correlated with a decrease in PANSS negative (r = 0.58, P = .02), general (r = 0.53, P = .04), and total symptom scores (r = 0.063, P = .01). Higher dopamine release in substantia nigra/ventral tegmental area predicted larger reductions in general symptoms (r = 0.51, P = .05). Post-amphetamine binding in putamen correlated positively with negative symptom scores at baseline (r = 0.66, P = .005) and throughout all follow-up visits. Conclusions These exploratory results support a relationship between d-amphetamine-induced dopamine release and the severity and persistence of symptoms during the first year of psychosis.

Context: No long-term studies have compared centrally acting drugs for treating obesity. Objective: To compare the efficacy and safety of diethylpropion (DEP), fenproporex (FEN), mazindol (MZD), fluoxetine (FXT) and sibutramine (SIB) in promoting weight loss. Design and Setting: A prospective, randomized, placebo (PCB)-controlled study conducted at a single academic institution. Patients: A total of 174 obese premenopausal women. Intervention: Participants randomly received DEP 75 mg ( n =28), FEN 25 mg ( n =29), MZD 2 mg ( n =29), SIB 15 mg ( n =30), FXT 20 mg ( n =29) or PCB ( n =29) daily over 52 weeks. Diet and physical activity were encouraged. Main Outcome Measures: The primary endpoints were changes in body weight and the proportion of women who achieved at least 5% weight loss by week 52 in the intent-to-treat population. Other measurements included anthropometry, safety, metabolic and cardiovascular parameters. Results: Weight loss was greater than PCB (−3.1±4.3 kg) with DEP (−10.0±6.4 kg; P< 0.001), SIB (−9.5±5.9 kg; P< 0.001), FEN (−7.8±6.9 kg; P< 0.01) and MZD (−7.4±4.9 kg; P< 0.01) but not with FXT (−2.5±4.1 kg). Ten (33.3%) women lost⩾5% of their initial weight with PCB, compared with 20 (71.4%; P< 0.001) with DEP, 20 (69%; P< 0.02) with FEN, 21 (72.4%; P< 0.01) with MZD, 22 (73.3%; P< 0.001) with SIB and 10 (35.5%) with FXT. Each medically treated group experienced more adverse events compared with PCB ( P< 0.001). Compared with PCB, constipation was more prevalent with DEP, SIB and MZD ( P< 0.01); anxiety was more prevalent with DEP ( P= 0.01); and irritability occurred more frequently with DEP and FEN ( P= 0.02). Significant improvements in the depression and anxiety scores, binge-eating episodes and quality of life correlated with weight loss. CONCLUSION: The centrally acting drugs DEP, FEN, MZD and SIB were more effective than PCB in promoting weight loss in obese premenopausal women, with a satisfactory benefit–risk profile.

Objective: To compare the dose effects of long-acting extended-release dexmethylphenidate (ER d-MPH) and ER mixed amphetamine salts (ER MAS) on attention-deficit/hyperactivity disorder (ADHD) symptom dimensions, global and specific impairments, and common adverse events associated with stimulants. Methods: Fifty-six children and adolescents with ADHD participated in an 8-week, double-blind, crossover study comparing ER d-MPH (10, 20, 25–30 mg) and ER MAS (10, 20, 25–30) with a week of randomized placebo within each drug period. Efficacy was assessed with the ADHD Rating Scale-IV (ADHD-RS-IV), whereas global and specific domains of impairment were assessed with the Clinical Global Impressions Severity and Improvement Scales and the parent-completed Weiss Functional Impairment Scale, respectively. Insomnia and decreased appetite, common stimulant-related adverse events, were measured with the parent-completed Stimulant Side Effects Rating Scale. Results: Both ER d-MPH and ER MAS were associated with significant reductions in ADHD symptoms. Improvement in Total ADHD and Hyperactivity/Impulsivity symptoms were strongly associated with increasing dose, whereas improvements in Inattentive symptoms were only moderately associated with dose. About 80% demonstrated reliable change on ADHD-RS-IV at the highest dose level of ER MAS compared with 79% when receiving ER d-MPH. Decreased appetite and insomnia were more common at higher dose levels for both stimulants. Approximately 43% of the responders were preferential responders to only one of the stimulant formulations. Conclusions: Dose level, rather than stimulant class, was strongly related to medication response.

Objective: The purposes of this study were to examine the impact of 3 weeks of amphetamine administration on intrinsic connectome-wide connectivity patterns in adults with attention-deficit/hyperactivity disorder (ADHD) and explore the association between stimulant-induced symptom improvement and functional connectivity alteration. Methods: Participants included 19 adults (age 20–55 years) diagnosed with ADHD using the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) criteria per the Adult Clinician Diagnostic Scale taking part in amphetamine trials. For each patient, two 6-minute resting-state functional magnetic resonance imaging (R-fMRI) scans were acquired at baseline and after treatment. A fully data-driven multivariate analytic approach (i.e., multivariate distance matrix regression [MDMR]) was applied to R-fMRI data to characterize the distributed pharmacological effects in the entire functional connectome. Clinical efficacy was assessed using ADHD rating scale with adult prompts and the Adult Self-Report Scale v1.1 Symptom Checklist. We linked stimulant-induced functional connectivity changes to symptom amelioration using Spearman's correlation. Results: Three weeks of administration of a stimulant significantly reduced ADHD symptoms. MDMR-based analyses on R-fMRI data highlighted the left dorsolateral prefrontal cortex (DLPFC, a key cognitive control region) and the medial prefrontal cortex (MPFC, the anterior core of default network) whose distributed patterns of functional connectivity across the entire brain were altered by psychostimulants. Follow-up intrinsic functional connectivity revealed that stimulants specifically decreased the positive functional connectivity between DLPFC–insula, DLPFC–anterior cingulate cortex, and MPFC–insula. Importantly, these functional connectivity changes are associated with symptom improvement. Conclusion: These results suggested that ADHD is associated with increased functional integration or decreased functional segregation between core regions of cognitive control, default, and salience networks. The apparent normalization of intrinsic functional interaction in these circuits (i.e., increased functional segregation) may underlie the clinical benefits produced by 3 weeks of amphetamine treatment.

Rationale Adderall (mixed amphetamine salts) is used by healthy normal individuals to enhance attention. Research with healthy normal participants and those with attention deficit hyperactivity disorder indicate a possible inverse relationship between attentional function and creativity. This raises the possibility that Adderall could decrease creativity in people using it for cognitive enhancement. Objective This study was designed to find out whether Adderall impairs creativity in healthy young adults. Material and methods In a double-blind placebo-controlled study, the effects of Adderall on the performance of 16 healthy young adults were measured on four tests of creativity from the psychological literature: two tasks requiring divergent thought and two requiring convergent thought. Results Adderall affected performance on the convergent tasks only, in one case enhancing it, particularly for lower-performing individuals, and in the other case enhancing it for the lower-performing and impairing it for higher-performing individuals. Conclusion The preliminary evidence is inconsistent with the hypothesis that Adderall has an overall negative effect on creativity. Its effects on divergent creative thought cannot be inferred with confidence from this study because of the ambiguity of null results. Its effects on convergent creative thought appear to be dependent on the baseline creativity of the individual. Those in the higher range of the normal distribution may be unaffected or impaired, whereas those in the lower range of the normal distribution experience enhancement.

AIM:: This article provides the first comprehensive meta-analysis of randomized clinical trials of medications for obesity. METHOD:: Based on stringent inclusionary criteria, a total of 108 studies were included in the final database. Outcomes are presented for comparisons of single and combination drugs to placebo and for comparisons of medications to one another. RESULT:: Overall, the medications studied produced medium effect sizes. Four drugs produced large effect sizes (ie d>0.80; amphetamine, benzphetamine, fenfluramine and sibutramine). The placebo-subtracted weight losses for single drugs vs placebo included in the meta-analysis never exceeded 4.0 kg. No drug, or class of drugs, demonstrated clear superiority as an obesity medication. Effects of methodological factors are also presented along with suggestions for future research. INTERNATIONAL JOURNAL OF OBESITY: (2002) 26, 262-273. DOI: 10.1038/sj.ijo.0801889

Objective: To determine whether amphetamine extended-release oral suspension (AMPH EROS) has an onset of effect at 30 minutes postdose in children with attention-deficit/hyperactivity disorder (ADHD). Methods: This randomized, double-blind, two-treatment, two-sequence, placebo-controlled crossover pilot study enrolled subjects aged 6–12 years with ADHD and ADHD-Rating Scale-5 scores of ≥90th percentile for sex and age. An optimized dose of 5–20 mg/day of AMPH EROS was determined during a 1-week open-label dose optimization phase based on medication history, symptom control, and tolerability. Subjects completed a practice laboratory classroom then received 1 day of double-blind active drug or placebo each in random sequence during two double-blind laboratory classroom days. Subjects completed the first double-blind laboratory classroom, returned to open-label drug for 5 days, and then crossed over on day 6 during a second double-blind laboratory classroom. Double-blind dose was fixed at AMPH EROS 15, 17.5, or 20 mg. The primary end point was change from predose in the Swanson, Kotkin, Agler, M-Flynn, Pelham-Combined (SKAMP-C) Rating Scale score at 30 minutes postdose on two double-blind days. The key secondary end points were change from predose in the SKAMP-C score at 3 hours postdose for AMPH EROS compared with placebo and change from baseline Permanent Product Measure of Performance (PERMP) scores at 30 minutes and 3 hours postdose compared with placebo. Safety assessments included vital signs and adverse events (AEs). Results: Eighteen subjects were enrolled in the study (14 males and 4 females) with a mean age of 9 years. At both 30 minutes and 3 hours postdose, changes from baseline in SKAMP-C for AMPH EROS versus placebo were statistically significant (p < 0.01 and p = 0.0002, respectively). PERMP scores were not statistically significantly improved at 30 minutes postdose for AMPH EROS relative to the placebo group. PERMP scores were statistically significantly improved at 3 hours postdose for AMPH EROS relative to the placebo group (PERMP problems attempted treatment difference least-squares [LS] mean [SE] = 60.3 [12.93], p = 0.0003; PERMP problems correct treatment difference LS mean [SE] = 61.6 [13.16], p = 0.0003). AEs (>10%) during the open-label phase included upper respiratory tract infection, fatigue, upper abdominal pain, headache, decreased appetite, and affect lability. Conclusions: AMPH EROS was effective in reducing ADHD symptoms at 30 minutes postdose as indicated by SKAMP-C score improvement, although improvements in PERMP scores at 30 minutes were not statistically significant. AEs were mild or moderate and consistent with those of other extended-release amphetamines.

Objective: The study goal was to determine the efficacy and safety of an optimal dose of Evekeo, racemic amphetamine sulfate, 1:1 d-amphetamine and l-amphetamine (R-AMPH), compared to placebo in treating children with attention-deficit/hyperactivity disorder (ADHD) in a laboratory classroom setting. Methods: A total of 107 children ages 6–12 years were enrolled in this multicenter, dose-optimized, randomized, double-blind, placebo-controlled crossover study. After 8 weeks of open-label dose optimization, 97 subjects were randomized to 2 weeks of double-blind treatment in the sequence of R-AMPH followed by placebo (n=47) or placebo followed by R-AMPH (n=50). Efficacy measures included the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale and Permanent Product Measure of Performance (PERMP) administered predose and at 0.75, 2, 4, 6, 8, and 10 hours postdose on 2 laboratory classroom days. Safety assessments included physical examination, chemistry, hematology, vital signs, and treatment-emergent adverse events (TEAEs). Results: Compared to placebo, a single daily dose of R-AMPH significantly improved SKAMP-Combined scores (p<0.0001) at each time point tested throughout the laboratory classroom days, with effect onset 45 minutes postdose and extending through 10 hours. R-AMPH significantly improved PERMP number of problems attempted and correct (p<0.0001) throughout the laboratory classroom days. During the twice-daily dose-optimization open-label phase, improvements were observed with R-AMPH in scores of the ADHD-Rating Scale IV and Clinical Global Impressions Severity and Improvement Scales. TEAEs and changes in vital signs associated with R-AMPH were generally mild and not unexpected. The most common TEAEs in the open-label phase were decreased appetite (27.6%), upper abdominal pain (14.3%), irritability (14.3%), and headache (13.3%). Conclusions: Compared to placebo, R-AMPH was effective in treating children aged 6–12 years with ADHD, beginning at 45 minutes and continuing through 10 hours postdose, and was well tolerated. Trial registration: ClinicalTrials.gov identifier: NCT01986062. https://clinicaltrials.gov/ct2/show/NCT01986062

Objectives: This study seeks to determine if variation in the dopamine transporter gene (SLC6A3/DAT1) moderates the dose-response effects of long-acting dexmethylphenidate (D-MPH) and mixed amphetamine salts (MAS) in children with attention-deficit/hyperactivity disorder (ADHD). Methods: Fifty-six children and adolescents (mean age=11.7±2.2) participated in a double-blind, two period crossover, dose-response study with a randomized placebo week in each 4 week drug period. Each period consisted of sequential week-long exposures to three dose levels (10, 20, 25–30 mg, depending upon weight) of D-MPH or MAS. Results: Doses of 10–20 mg of either D-MPH or MAS had little to no effect on hyperactivity-impulsivity and total ADHD symptom scores in subjects with the 9/9 genotype; this was in contrast to the dose-response curves of subjects with either the 10/10 or 10/9 genotype. Conclusions: ADHD youth with the 9/9 genotype may require higher stimulant doses to achieve adequate symptom control.

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, parallelgroup, 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≤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≤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.