Distinguishing the efficacy and sedative effects of guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder

The present study investigated whether symptom reduction in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) treated with guanfacine extended release (GXR) can be explained by sedative effects of the medication. Data from four double-blind, randomized, placebo-controlled, phase 3 trials of GXR monotherapy (1–7 mg/day; morning administration) in children (aged 6–12 years) and adolescents (aged 13–17 years) with ADHD were analyzed post hoc. Two studies used forced-dose titration and two used flexible-dose titration. Efficacy was determined using ADHD Rating Scale IV (ADHD-RS-IV) scores. Sedative treatment-emergent adverse events (TEAEs) included somnolence, sedation and hypersomnia. The proportion of responders (≥ 30% reduction in ADHD-RS-IV total score) increased from weeks 1 to 4 and remained stable to study endpoint. Sedative TEAEs generally peaked at the first week in which the target dose was achieved and then declined. In subgroup analyses, significant placebo-adjusted improvements in ADHD-RS-IV total scores were observed in participants without any sedative TEAEs in the forced-dose and flexible-dose studies (nominal p < 0.001). In addition, GXR was associated with significant improvements in both inattentive and hyperactive–impulsive symptoms, as assessed by the ADHD-RS-IV subscale scores (nominal p < 0.001) and by the ADHD-RS-IV total score in participants with different ADHD subtypes (nominal p < 0.05). Thus, the efficacy of GXR in children and adolescents with ADHD is not primarily due to sedation, although some contribution to symptom reduction cannot be excluded, especially early in treatment when rates of sedative TEAEs are at their highest.     

Dexmethylphenidate extended release: in attention-deficit hyperactivity disorder

Dexmethylphenidate extended release (XR) is an orally administered, bimodal release, capsule formulation of the active d-enantiomer of methylphenidate (MPH), which inhibits dopamine and norepinephrine (noradrenaline) reuptake to increase their concentration in the extraneuronal space. A single dose of dexmethylphenidate XR mimics the pharmacokinetic profile of two doses of dexmethylphenidate immediate-release formulation administered 4 hours apart, albeit with less fluctuation in plasma concentration. Once-daily dexmethylphenidate XR was more effective than placebo in reducing attention-deficit hyperactivity disorder (ADHD) symptom scores in children, adolescents and adults with ADHD in four randomised, double-blind, placebo-controlled trials of up to 7 weeks' duration. In crossover trials in children (aged 6-12 years), dexmethylphenidate XR 20 mg/day reduced mean ADHD symptom scores 1 hour after administration (by 43% in one trial) and was significantly better than placebo for up to 12 hours. Dexmethylphenidate XR 5-30 mg/day reduced mean ADHD symptom scores by 49%, while scores declined by 16% with placebo in a 7-week trial in children and adolescents (aged 6-17 years). Dexmethylphenidate XR 20, 30 or 40 mg/day reduced ADHD symptom scores by 36-46% versus a 21% reduction with placebo in a 5-week trial in adults (aged 18-60 years). Dexmethylphenidate XR was generally well tolerated in children, adolescents and adults with ADHD, with an adverse-event profile typical of MPH.     

Valsartan: in children and adolescents with hypertension

Valsartan is an oral angiotensin II subtype 1 receptor antagonist with well established antihypertensive efficacy in adults. It is now approved in the EU and the US for the treatment of hypertension in children and adolescents. In two, randomized, double-blind trials, a once-daily regimen of valsartan reduced the blood pressure (BP) of children and adolescents with hypertension. In one trial in hypertensive children and adolescents aged 6-16 years, significant dose-dependent reductions from baseline in mean sitting systolic BP (msSBP) were observed for recipients of valsartan following 2 weeks' treatment (primary endpoint). There were corresponding dose-dependent and significant reductions in mean sitting diastolic BP. Following 2 further weeks of treatment, the reduction in msSBP was maintained in patients who were re-randomized to continue receiving the same dosage of valsartan but not in those re-randomized to placebo. In the other trial in hypertensive children and adolescents aged 6-17 years, valsartan was no less effective than enalapril in reducing BP. Following 12 weeks' treatment, the least square mean reduction from baseline in msSBP (primary endpoint) in recipients of valsartan was noninferior to that in recipients of enalapril. In addition, the proportion of patients achieving an msSBP <95th percentile for age, sex, and height at week 12 was not significantly different between recipients of valsartan and enalapril (67% vs 70%). Treatment with valsartan for up to 52 weeks was well tolerated in children and adolescents with hypertension.     

European,randomized, phase 3 study of lisdexamfetamine dimesylate in children and adolescents with attention-deficit/hyperactivity disorder

This study evaluated the efficacy and safety of lisdexamfetamine dimesylate (LDX) compared with placebo in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) in Europe. Osmotic-release oral system methylphenidate (OROS-MPH) was included as a reference arm. Patients (6–17 years old) with a baseline ADHD Rating Scale version IV (ADHD-RS-IV) total score ≥28 were randomized (1:1:1) to dose-optimized LDX (30, 50, or 70 mg/day), OROS-MPH (18, 36, or 54 mg/day) or placebo for 7 weeks. Primary and key secondary efficacy measures were the investigator-rated ADHD-RS-IV and the Clinical Global Impressions-Improvement (CGI-I) rating, respectively. Safety assessments included treatment-emergent adverse events (TEAEs), electrocardiograms, and vital signs. Of 336 patients randomized, 196 completed the study. The difference between LDX and placebo in least squares mean change in ADHD-RS-IV total score from baseline to endpoint was ?18.6 (95% confidence interval [CI]: ?21.5 to ?15.7) (p<0.001; effect size, 1.80). The difference between OROS-MPH and placebo in least squares mean change in ADHD-RS-IV total score from baseline to endpoint was ?13.0 (95% CI: ?15.9 to ?10.2) (p<0.001; effect size, 1.26). The proportions (95% CI) of patients showing improvement (CGI-I of 1 or 2) at endpoint were 78% (70–86), 14% (8–21), and 61% (51–70) for LDX, placebo, and OROS-MPH. The most common TEAEs for LDX were decreased appetite, headache, and insomnia. Mean changes in vital signs were modest and consistent with the known profile of LDX. LDX was effective and generally well tolerated in children and adolescents with ADHD.     

Methylphenidate transdermal system: in attention-deficit hyperactivity disorder in adolescents

Methylphenidate transdermal system uses DOT Matrix? technology and, once applied to the skin, releases methylphenidate continuously. In the US, methylphenidate transdermal system is indicated for use in the treatment of attention-deficit hyperactivity disorder (ADHD). According to the results of a randomized, double-blind, multicentre, 7-week trial (core trial), methylphenidate transdermal system 10-30?mg was effective in adolescents aged 13-17 years with ADHD. The mean ADHD-Rating Scale-IV (ADHD-RS-IV) total score (primary endpoint) decreased to a significantly greater extent in adolescents receiving methylphenidate transdermal system than in those receiving placebo transdermal system. Following the core trial, adolescents could subsequently receive methylphenidate transdermal system in an extension study of ≈6 months duration. From the start of the core trial to the end of the extension study, methylphenidate transdermal system recipients demonstrated a significant reduction in the mean ADHD-RS-IV total score. Methylphenidate transdermal system was generally well tolerated in adolescents with ADHD. The vast majority of treatment-emergent adverse events were of mild to moderate severity in both the short-term core trial and the longer-term extension study.     

Efficacy of extended release quetiapine fumarate monotherapy in patients with major depressive disorder: a pooled analysis of two 6-week, double-blind, placebo-controlled studies

Prospectively planned pooled analysis evaluating the efficacy of quetiapine extended release (XR) monotherapy in major depressive disorder (MDD). Data were pooled from two 6-week, randomized, double-blind, placebo-controlled studies of quetiapine XR in outpatients with MDD. The primary endpoint was Montgomery-?sberg Depression Rating Scale (MADRS) total score change from randomization at week 6. Other evaluations were MADRS response/remission, Hamilton Rating Scale for Anxiety, and subgroup analyses. A total of 968 patients were randomized to quetiapine XR, 150 mg/day (n=315), 300 mg/day (n=323), or placebo (n=330). The mean MADRS total score reductions from randomization were significant at week 6 with quetiapine XR, 150 mg/day (-14.7; P<0.001) and 300 mg/day (-14.7; P<0.001) versus placebo (-11.1), with significant reductions versus placebo from week 1 onward. Response rates (week 6): 52.7% (P<0.001) quetiapine XR 150 mg/day and 49.5% (P<0.001) quetiapine XR 300 mg/day versus placebo (33.0%). MADRS remission (score≤8; week 6): 23.5% (P=0.208) quetiapine XR 150 mg/day and 28.8% (P<0.01) quetiapine XR 300 mg/day versus placebo (19.4%). Quetiapine XR (both doses) significantly improved eight of 10 MADRS items versus placebo at week 6. The therapeutic effect of quetiapine XR was neither limited to nor driven by factors such as sex, age, or severity of depression. In patients with MDD, quetiapine XR (150 and 300 mg/day) monotherapy reduced depressive symptoms, with significant improvements compared with placebo from week 1 onward.     

Pharmacotherapy of attention-deficit hyperactivity disorder in adolescents

Attention-deficit hyperactivity disorder (ADHD) is a common neurobehavioural disorder in children and adolescents, consisting of developmentally inappropriate levels of inattention and/or hyperactivity and impulsivity. The majority of children with ADHD will continue to experience significant ADHD symptoms as teens. ADHD in adolescents can result in significant functional impairment and poorer quality of life. Children and adolescents with ADHD are at higher risk of developing other psychiatric illnesses such as mood, conduct and substance abuse disorders. Stimulants (amphetamines and methylphenidates) and nonstimulants (atomoxetine, guanfacine extended-release (XR) and clonidine XR) have been found to be effective and are approved by the US FDA for the treatment of ADHD in adolescents in the US. Of the agents approved in the US, only guanfacine XR and clonidine XR are not approved in any other countries. There is growing evidence that treatment of ADHD with stimulants reduces the risk of development of other psychiatric co-morbidities, including substance abuse disorders. To date, all FDA-approved stimulants and nonstimulants that have been adequately studied have been demonstrated to be safe and effective in treating ADHD in both children and adolescents. Therefore, clinical decisions used in selecting pharmacotherapy to treat ADHD in children aged 6-12 years can be applied in the adolescent population.     

Dexmethylphenidate

Dexmethylphenidate comprises only the d-enantiomer (the pharmacologically effective isomer) of racemic methylphenidate and is indicated for the treatment of patients aged > or =6 years with attention deficit hyperactivity disorder (ADHD). In a 4-week, double-blind trial in 132 children with ADHD, significantly greater improvements from baseline in teacher-rated Swanson, Nolan and Pelham (SNAP)-ADHD scores were seen in dexmethylphenidate and methylphenidate recipients, compared with placebo recipients. In addition, significantly more dexmethylphenidate and methylphenidate recipients, compared with placebo recipients, were much improved or very much improved according to Clinical Global Impression-Improvement of Illness scale scores. In the same study, parent-rated SNAP-ADHD scores had decreased by a significantly greater extent in dexmethylphenidate recipients at 3pm and 6pm and in methylphenidate recipients at 3pm, compared with placebo recipients. Significantly fewer dexmethylphenidate than placebo recipients failed treatment in a double-blind, treatment-withdrawal trial in 75 children with ADHD (17.1 vs 61.5%). In a noncomparative study in 22 children with ADHD, symptoms of ADHD, as assessed by teachers and parents, were controlled during the entire school day in 68 and 86% of dexmethylphenidate recipients, respectively, with a median duration of effect of 6.3 and 7.5 hours, respectively. Dexmethylphenidate was generally well tolerated in children with ADHD; adverse events were consistent with those known to be associated with agents containing methylphenidate.     

Quetiapine: a review of its use in the management of bipolar depression

Quetiapine (Seroquel?) is an orally administered atypical antipsychotic that is indicated for the treatment of schizophrenia and bipolar disorder, including bipolar depression. An extended-release (XR) formulation of quetiapine is also available. This review summarizes the pharmacological properties, efficacy and tolerability of quetiapine and quetiapine XR in patients with bipolar depression. Quetiapine is an antagonist at both serotonin 5-HT2 and dopamine D2 receptors, and its antipsychotic effects are thought to stem from interactions at these receptors. The antidepressant effects of quetiapine are poorly understood, but may be related to antagonism of 5-HT2A receptors in cortical regions, partial agonism of 5-HT1A in the prefrontal cortex in association with increased extracellular dopamine release in the region, or to reduced synaptic reuptake of noradrenaline resulting from inhibition of the noradrenaline reuptake transporter by the quetiapine metabolite norquetiapine. The efficacy and tolerability of quetiapine was evaluated in five 8-week, randomized, double-blind, placebo-controlled, multicentre or multinational trials in patients with a major depressive episode (MDE) associated with bipolar disorder. Across trials, monotherapy with oral quetiapine 300 or 600?mg/day (or quetiapine XR 300?mg/day) produced significantly greater improvements than placebo in depressive symptoms (primary endpoint), according to the change in the Montgomery-Asberg Depression Rating Scale total score. In general, quetiapine and quetiapine XR were also associated with significantly higher MDE response and remission rates than placebo. Across trials, quetiapine and quetiapine XR produced significantly greater improvements in global severity of illness scores than placebo, according to changes in the Clinical Global Impressions scale score. There were no differences in treatment outcomes between quetiapine 300?mg/day and 600?mg/day dosage groups. Patients with bipolar depression who responded to quetiapine during two 8-week acute treatment trials also benefited from continuing quetiapine therapy for up to 52 weeks. Compared with quetiapine responders randomized to placebo, quetiapine responders who continued quetiapine 300 or 600?mg/day had a significantly reduced risk of recurrence of any mood events and of depression mood events, but not of hypomanic/manic events. In a randomized, double-blind, placebo-controlled trial, quetiapine maintenance therapy for up to 104 weeks was more efficacious than placebo or lithium in prolonging the time to recurrence of any mood event (primary endpoint). Patients in this trial had bipolar I disorder with mania, depression or a mixed episode as the index episode, and the trial included only patients who were responsive to acute phase quetiapine, which may have introduced a positive bias in favour of quetiapine over lithium during maintenance therapy. Quetiapine 300 or 600?mg/day and quetiapine XR 300?mg/day was generally well tolerated in patients with bipolar depression, with most treatment-emergent adverse events being of mild to moderate severity. The most frequent adverse events occurring during the acute treatment phase were dry mouth, sedation, somnolence, dizziness (quetiapine and quetiapine XR), constipation (quetiapine) and increased appetite (quetiapine XR). Extrapyramidal symptoms (EPS) occurred across quetiapine and placebo groups, but there were no significant differences between quetiapine and placebo recipients on objective measures of EPS and akathisia. In some trials, quetiapine recipients experienced significantly greater weight gain than placebo recipients. Across trials, some quetiapine recipients had clinically relevant increases in blood glucose or lipid parameters, although these also occurred in patients from other treatment groups. The clinical significance of these changes is uncertain. In conclusion, quetiapine and quetiapine XR are valuable additions to the first-line treatments for bipolar depression. Further head-to-head trials of quetiapine versus other drug regimens that are effective in bipolar depression would be of considerable interest.     

A community assessment, open-label study of the safety, tolerability, and effectiveness of mixed amphetamine salts extended release in school-age children with ADHD

OBJECTIVE: To assess the safety, tolerability, and effectiveness of mixed amphetamine salts extended release (MAS XR) in school-age children with attention-deficit/hyperactivity disorder (ADHD) treated in a community practice setting. METHODS: Children aged 6-12 years (N = 2968) with DSM-IV-defined ADHD entered a 9-week prospective, open-label, non-comparative study of MAS XR at 386 sites. For at least 2 weeks before enrollment, subjects with well-controlled ADHD received their consistent dose of previously prescribed psychostimulant. Subsequently, this regimen was converted to an equivalent once-daily dose of 10-, 20-, or 30-mg MAS XR, according to a conversion algorithm. Tolerability and safety were assessed based on reported treatment-emergent adverse events and observed changes in vital signs and body weight. Effectiveness was assessed using a parent-completed Conners' Global Index Scale (CGIS-P) measured 8 and 12 h postdose and a clinician-scored Clinical Global Impressions-Improvement (CGI-I) scale after 1, 3, and 7 weeks of treatment. The dose of study medication could be adjusted at weeks 1 and 3 to a maximum of 40 mg/day. Outcome analyses used an intent-to-treat methodology, with last observations carried forward. RESULTS: Statistically significant improvement in ADHD behavior 8 and 12 h postdose occurred during the first week of treatment and was maintained through study endpoint (p < 0.0001). Results of the investigator-rated CGI-I at weeks 1, 3, and 7 were consistent with the parent-rated CGIS-P results, indicating that MAS XR treatment significantly improved symptoms compared with the baseline stimulant regimen (p < 0.0001). The incidence of treatment-related adverse events was low, and most AEs were mild in intensity. CONCLUSION: MAS XR 10-40 mg is a safe and effective once-daily medication for treatment of children with ADHD in a community practice setting. ADHD symptoms may be further reduced by converting from current pharmacotherapy to an optimally titrated dose of MAS XR.     

Quetiapine extended release: adjunctive treatment in major depressive disorder

Quetiapine extended release (XR) is a once-daily oral formulation of the atypical antipsychotic quetiapine that is available for use as adjunctive therapy in major depressive disorder (MDD). Systemic quetiapine exposure after orally administered quetiapine XR is similar to that of quetiapine immediate release at the same dosage, although quetiapine XR is absorbed more slowly and plasma concentrations are more stable over time. In two 6-week, randomized, double-blind, placebo-controlled, multinational trials in patients with MDD with an inadequate response to antidepressants, quetiapine XR 300?mg/day adjunctive to antidepressant reduced depressive symptoms significantly more than antidepressant plus placebo, according to changes in Montgomery-?sberg Depression Rating Scale (MADRS) total scores. In one trial, adjunctive quetiapine XR 150?mg/day also led to significantly greater reductions in MADRS total scores than antidepressant plus placebo. MDD response rates were significantly higher with adjunctive quetiapine XR 300?mg/day (but not 150?mg/day) than with antidepressant plus placebo. The numbers needed to treat to achieve an additional response over antidepressant plus placebo were 11-18 and 8-9 in the quetiapine XR 150 and 300?mg/day dosage groups, respectively. Treatment-emergent adverse events were mostly of mild to moderate severity; 1% of adjunctive quetiapine XR and 1.3% of antidepressant plus placebo recipients reported serious adverse events.     

Rotigotine: in Parkinson's disease

Rotigotine is a nonergolinic dopamine D3/D2/D1 receptor agonist delivered via a transdermal system and has been evaluated for the treatment of idiopathic Parkinson's disease. Patients with early Parkinson's disease receiving rotigotine monotherapy experienced significantly greater improvements in parkinsonian symptoms (as measured by Unified Parkinson's Disease Rating Scale scores) compared to placebo in two large, well designed clinical trials. Significant beneficial effects versus placebo were observed with the 30 and 40 cm2 rotigotine patches in both trials.black triangle Patients with advanced Parkinson's disease receiving rotigotine as adjunctive therapy with levodopa experienced clinically significant reductions from baseline in 'off' time in two well designed clinical trials. In one trial, a large placebo effect was observed, therefore, there was no significant difference between placebo and active treatment (20, 40 and 60 cm2) for this primary efficacy variable, However, a recent study found a significant (p < or = 0.003) reduction in 'off' time in rotigotine 40 and 60 cm2 recipients versus that in the placebo group. Rotigotine was generally well tolerated in clinical trials as both monotherapy and when administered with levodopa; adverse events were generally mild or moderate in severity.     

Escitalopram versus venlafaxine XR in the treatment of depression

This article reanalyses and reviews data from the two published randomized clinical trials comparing escitalopram and venlafaxine XR in the treatment of patients with major depressive disorder. The aim was to further compare the efficacy and tolerability of escitalopram and venlafaxine XR and to assess the impact of the two treatments on the patient's quality of life, as well as the benefit/risk of treatment. A total of 243 escitalopram-treated patients and 240 venlafaxine XR-treated patients were included in this analysis. Comparable treatment efficacy was achieved with respect to the prospectively defined primary efficacy endpoint (mean change from baseline in Montgomery Asberg Depression Rating Scale (MADRS) total score at week 8). An analysis of the outcome at the end of study by baseline severity showed that the treatment difference became greater the more severely depressed the patients were at baseline. At the highest permitted doses, in the subgroup of patients who were severely depressed (baseline MADRS > or =30), patients treated with escitalopram had a statistically significantly greater improvement (P<0.05) in mean MADRS total scores than patients treated with venlafaxine XR at endpoint. For these patients, treatment with 20 mg/day escitalopram resulted in a statistically significantly (P<0.05) higher remission rate at week 8 (47%) than treatment with venlafaxine XR (29%). This difference was confirmed by the analysis of the pooled data, which showed that patients in the escitalopram group had a significantly (P<0.05) higher mean number of depression-free days (30.4 days) than those in the venlafaxine XR group (26.2 days) over the 8-week period. The relative benefit of escitalopram versus venlafaxine XR was 1.46, indicating that a patient was more likely to benefit from treatment with escitalopram. The proportions of patients who withdrew owing to adverse events were 7.5% in the escitalopram group and 11.2% in the venlafaxine XR group. The mean number of discontinuation emergent signs and symptoms in the venlafaxine XR group (mean: 5.0) was significantly (P<0.001) higher than for the escitalopram group (mean: 2.4).     

Efficacy and tolerability of extended release quetiapine fumarate monotherapy in the acute treatment of generalized anxiety disorder: a randomized, placebo controlled and active-controlled study

The main objective of this study was to evaluate efficacy and tolerability of once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy in generalized anxiety disorder (GAD). This was a 8 week randomized, 2-week follow-up, double-blind, placebo-controlled, and active-controlled study. Patients were randomized to quetiapine XR 150 (n=219) or 300 mg/day (n=207); escitalopram, 10 mg/day (n=213); or placebo (n=215). The primary endpoint was the change from randomization at week 8 in Hamilton Anxiety Rating (HAM-A) total score. Week 8 mean HAM-A total score was significantly reduced from randomization with quetiapine XR 150 mg/day (-13.9, P<0.001), 300 mg/day (-12.3, P<0.05) and escitalopram (-12.3, P<0.05) versus placebo (-10.7); significant improvements with quetiapine XR (150 and 300 mg/day) versus placebo (P<0.001) were also shown at day 4. At week 8, significant improvements versus placebo were observed in HAM-A psychic [quetiapine XR (both doses) and escitalopram] and somatic (quetiapine XR 150 mg/day and escitalopram) cluster scores and HAM-A response and remission rates (quetiapine XR 150 mg/day). Most common adverse events were dry mouth, somnolence and sedation (quetiapine XR), headache, and nausea (escitalopram). In patients with GAD, quetiapine XR (150 and 300 mg/day) demonstrated significant efficacy at week 8 with symptom improvement as early as day 4. We concluded that quetiapine XR safety and tolerability results were consistent with the known profile of quetiapine.     

Aripiprazole: in adolescents with schizophrenia

Aripiprazole is a novel atypical antipsychotic that is approved in the US for use in adolescents with schizophrenia. In adolescents with schizophrenia, oral aripiprazole 10 or 30 mg/day lead to significantly greater reductions than placebo in the Positive and Negative Syndrome Scale (PANSS) total score from baseline to 6 weeks, according to findings from a randomized, double-blind, multicenter trial (n = 302). In addition, aripiprazole 10 or 30 mg/day recipients had significantly greater improvements in the PANSS positive subscale and Clinical global Impression-Severity and -Improvement scale scores than placebo recipients, and a significantly greater improvement in the PANSS negative subscale score was seen with aripiprazole 10 mg/day than with placebo. Aripiprazole was generally well tolerated in adolescents with schizophrenia, with most adverse events being of mild to moderate severity. Clinically significant weight gain (> or = 7% as defined by the US FDA) occurred in 4.0% of aripiprazole 10 mg/day recipients, 5.2% of aripiprazole 30 mg/day recipients, and 1% of placebo recipients. The mean weight change was significantly different in aripiprazole and placebo recipients (0, +2, and -0.8 kg in aripiprazole 10 mg/day, aripiprazole 30 mg/day, and placebo recipients, respectively).     

Montelukast: a review of its therapeutic potential in persistent asthma

Montelukast is a cysteinyl leukotriene receptor antagonist used to treat persistent asthma in patients aged > or = 6 years. The drug has a rapid onset of action. Improvements in lung function and reductions in as-needed beta2-agonist usage are apparent within 1 day of initiating montelukast treatment in adults and adolescents (aged > or = 15 years treated with 10 mg/day) or children (aged 6 to 14 years treated with 5 mg/day) with persistent asthma as shown in clinical trials. In two 12-week, multicentre, randomised, double-blind studies in adults and adolescents aged > or = 15 years with persistent asthma [forced expiratory volume in 1 second (FEV1) = 50 to 85% predicted] there was significantly (p < 0.05) greater improvement in FEV1, symptom scores, peak expiratory flow (PEF), as-needed beta2-agonist use, peripheral eosinophil counts and health-related quality of life (QOL) in patients treated with montelukast 10 mg/day than in recipients of placebo. Improvements were significantly greater in patients treated with inhaled beclomethasone 400 microg/day than in recipients of montelukast 10 mg/day in 1 of these studies. Nonetheless, 42% of montelukast recipients experienced > or = 11% improvement in FEV1, the median improvement in this parameter in beclomethasone-treated patients. In an 8-week multicentre, randomised, double-blind, study in children aged 6 to 14 years with persistent asthma (FEV1 50 to 85% predicted), montelukast 5 mg/day produced significantly greater improvements in FEV1, clinic PEF, as-needed beta2-agonist use, peripheral eosinophil counts, asthma exacerbations and QOL scores than placebo. The combination of montelukast 10 mg/day plus inhaled beclomethasone 200 microg twice daily provided significantly better asthma control than inhaled beclomethasone 200 microg twice daily in adults with poorly controlled asthma (mean FEV1 = 72% predicted) despite 4 weeks treatment with inhaled beclomethasone. Patients receiving the combination experienced significant improvements in FEV1 and morning PEF, significant reductions in daytime symptom scores, as-needed beta2 agonist usage and night-time awakenings with asthma, and had significantly lower peripheral blood eosinophil counts after 16 weeks in this multicentre, randomised, double-blind, placebo-controlled study. Among adults (FEV1 > or = 70%) treated with montelukast 10 mg/day for 12 weeks, inhaled corticosteroid dosages were titrated downward by 47% (vs 30% in placebo recipients), 40% of patients were tapered off of inhaled corticosteroids (vs 29%), and significantly fewer patients (16 vs 30%) experienced failed corticosteroid rescues in a multicentre, randomised, double-blind study. During clinical studies, the frequency of adverse events in montelukast-treated adults, adolescents and children was similar to that in placebo recipients. In conclusion, montelukast is well tolerated and effective in adults and children aged > or = 6 years with persistent asthma including those with exercise-induced bronchoconstriction and/or aspirin sensitivity. Furthermore, montelukast has glucocorticoid sparing properties. Hence, montelukast, as monotherapy in patients with mild persistent asthma, or as an adjunct to inhaled corticosteroids is useful across a broad spectrum of patients with persistent asthma.     

Methylphenidate controlled-delivery capsules (EquasymXL, Metadate CD): a review of its use in the treatment of children and adolescents with attention-deficit hyperactivity disorder

Controlled-delivery methylphenidate (methylphenidate CD) [EquasymXL, Metadate CD], an oral stimulant, is approved in the US and EU to treat children aged>or=6 years who have been diagnosed with attention-deficit hyperactivity disorder (ADHD). Once-daily methylphenidate CD is generally well tolerated and effective in the treatment of children and adolescents with ADHD. Methylphenidate CD resulted in superior control of ADHD symptoms compared with osmotic release oral system (OROS) methylphenidate over a time period corresponding to that of an average school day in a laboratory classroom. In 3-week clinical trials conducted in a community setting, methylphenidate CD was superior to placebo and noninferior to methylphenidate immediate-release (IR) in the treatment of children and adolescents with ADHD. Thus, methylphenidate CD should be considered an important primary treatment on its own or in addition to behavioral and psychosocial interventions, for when a reduction in ADHD symptoms is required during the school day in preference to the evening.     

Spotlight on methylphenidate controlled-delivery capsules (Equasym XL, Metadate CD) in the treatment of children and adolescents with attention-deficit hyperactivity disorder

Controlled-delivery methylphenidate (methylphenidate CD) [Equasym XL, Metadate CD], an oral stimulant, is approved in the US and EU to treat children aged > or = 6 years who have been diagnosed with attention-deficit hyperactivity disorder (ADHD). Once-daily methylphenidate CD is generally well tolerated and effective in the treatment of children and adolescents with ADHD. Methylphenidate CD resulted in superior control of ADHD symptoms compared with osmotic release oral system (OROS) methylphenidate over a time period corresponding to that of an average school day in a laboratory classroom. In 3-week clinical trials conducted in a community setting, methylphenidate CD was superior to placebo and non-inferior to methylphenidate immediate-release in the treatment of children and adolescents with ADHD. Thus, methylphenidate CD should be considered an important primary treatment on its own or in addition to behavioural and psychosocial interventions, for when a reduction in ADHD symptoms is required during the school day in preference to the evening.     

Eight-week, placebo-controlled, double-blind comparison of the antidepressant efficacy and tolerability of bupropion XR and venlafaxine XR

The efficacy, safety and tolerability of bupropion XR and venlafaxine XR was assessed and compared with placebo in adult outpatients with major depressive disorder (MDD). Adults meeting DSM-IV criteria for MDD with a minimum Hamilton Depression Rating Scale (HAMD) 17-Item total score of > or =18 were randomized to eight weeks of double-blind treatment with either bupropion XR (150 mg/day), venlafaxine XR (75 mg/day) or placebo. At the end of the fourth week of treatment, a dosage increase to bupropion XR 300 mg/day or venlafaxine XR 150 mg/day was allowed if, in the opinion of the investigator, response was inadequate. The primary efficacy endpoint was mean change from baseline at week 8 in the Montgomery-Asberg Depression Rating Scale (MADRS) total score last observation carried forward (LOCF). Mean changes from baseline at week 8 (LOCF) in MADRS total score were statistically significant for bupropion XR and venlafaxine XR patients compared to the placebo group: -16.0 for bupropion XR (P = 0.006 vs placebo), -17.1 for venlafaxine XR (P < 0.001 vs placebo) and -13.5 for placebo. Secondary outcomes (including CGI-S, HAM-A, MEI, Q-LES-Q-SF, responder and remitter analyses) also improved significantly for both active treatment groups compared with placebo. The most frequently reported adverse events were dry mouth and insomnia for bupropion XR, and nausea, hyperhidrosis, fatigue, and insomnia for venlafaxine XR. In this double-blind, placebo-controlled trial, bupropion XR at doses up to 300 mg/day and venlafaxine XR at doses up to 150 mg/day demonstrated comparable antidepressant efficacy.