Efficacy and tolerability of lisdexamfetamine dimesylate in children with attention-deficit/hyperactivity disorder: sex and age effects and effect size across the day

<p>Abstract</p> <p>Background</p> <p>Efficacy and safety profiles by sex and age (6-9 vs 10-12 years) and magnitude and duration of effect by effect size overall and across the day of lisdexamfetamine dimesylate (LDX) vs placebo were assessed.</p> <p>Methods</p> <p>This study enrolled children (6-12 years) with attention-deficit/hyperactivity disorder (ADHD) in an open-label dose optimization with LDX (30-70 mg/d) followed by a randomized, double-blind, placebo-controlled, 2-way crossover phase. Post hoc analyses assessed interaction between sex or age and treatment and assessed effect sizes for Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) and Permanent Product Measure of Performance (PERMP) scales and ADHD Rating Scale IV measures. No corrections for multiple testing were applied on time points and subgroup statistical comparisons.</p> <p>Results</p> <p>129 participants enrolled; 117 randomized. Both sexes showed improvement on all assessments at postdose time points; females showed less impairment than males for SKAMP and PERMP scores in treatment and placebo groups at nearly all times. Both age groups improved on all assessments at postdose time points. Children 10-12 years had less impairment in SKAMP ratings than those 6-9 years. Treatment-by-sex interactions were observed at time points for SKAMP-D, SKAMP total, and PERMP scores; no consistent pattern across scales or time points was observed. LDX demonstrated significant improvement vs placebo, by effect size, on SKAMP-D from 1.5-13 hours postdose. The overall LS mean (SE) SKAMP-D effect size was -1.73 (0.18). In the dose-optimization phase, common (≥2%) treatment-emergent adverse events (TEAEs) in males were upper abdominal pain, headache, affect lability, initial insomnia, and insomnia; in females were nausea and decreased weight. During the crossover phase for those taking LDX, higher incidence (≥2% greater) was observed in males for upper abdominal pain and insomnia and in females for nausea and headache. Overall incidence of TEAEs in age groups was similar.</p> <p>Conclusion</p> <p>Apparent differences in impairment level between sex and age groups were noted. However, these results support the efficacy of LDX from 1.5 hours to 13 hours postdose in boys and girls with medium to large effect sizes across the day with some variability in TEAE incidence by sex.</p> <p>Trial Registration Number</p> <p>ClinicalTrials.gov Identifier: <a href="http://clinicaltrials.gov/ct2/show/NCT00500149">NCT00500149</a>.</p

Psychiatric and cognitive phenotype in children and adolescents with myotonic dystrophy

Myotonic dystrophy type 1 (DM1) is the most frequent inherited neuromuscular disorder. The juvenile form has been associated with cognitive and psychiatric dysfunction, but the phenotype remains unclear. We reviewed the literature to examine the psychiatric phenotype of juvenile DM1 and performed an admixture analysis of the IQ distribution of our own patients, as we hypothesised a bimodal distribution. Two-thirds of the patients had at least one DSM-IV diagnosis, mainly attention deficit/ hyperactivity disorder and anxiety disorder. Two-thirds had learning disabilities comorbid with mental retardation on one hand, but also attention deficit, low cognitive speed and visual spatial impairment on the other. IQ showed a bi-modal distribution and was associated with parental transmission. The psychiatric phenotype in juvenile DM1 is complex. We distinguished two different phenotypic subtypes: one group characterised by mental retardation, severe developmental delay and maternal transmission; and another group characterised by borderline full scale IQ, subnormal development and paternal transmission

Comparative phylogenetic methods and the cultural evolution of medicinal plant use

Human life depends on plant biodiversity and the ways in which plants are used are culturally determined. Whilst anthropologists have used phylogenetic comparative methods (PCMs) to gain an increasingly sophisticated understanding of the evolution of political, religious, social, and material culture, plant use has been almost entirely neglected. Medicinal plants are of special interest because of their role in maintaining people’s health across the world. PCMs in particular, and cultural evolutionary theory in general, provide a framework in which to study the diversity of medicinal plant applications cross-culturally, and to infer changes in plant use through time. These methods can be applied to single medicinal plants as well as the entire set of plants used by a culture for medicine, and they account for the non-independence of data when testing for floristic, cultural or other drivers of plant use. With cultural, biological, and linguistic diversity under threat, gaining a deeper and broader understanding of the variation of medicinal plant use through time and space is pressing

Is there a future for mGlu5-positive allosteric modulators in absence epilepsy? A comparison with ethosuximide

Contains fulltext : 175798.pdf (Publisher’s version ) (Open Access)Ethosuximide is the drug of choice in the treatment of various types of absence seizures. However, there is plenty of room for other anti-absence drugs, considering that not all subjects (57-74%) become seizure-free and about 47% of ethosuximide therapy fails. New anti-absence drugs may target or modulate glutamatergic and or GABAergic neurotransmission, the key players in the circuitry involved in the cortico-thalamo-cortical oscillations responsible for the highly stereotyped spike-wave discharges (SWDs). Cortical highly excitable cells in the focal region form the trigger for the occurrence of SWDs. In contrast, enhanced tonic inhibition is dominant in the thalamus. Biochemical studies have shown that symptomatic WAG/Rij rats differ from age-matched controls in metabotropic glutamate (mGlu) receptor expression and function: mGlu5 receptor expression and function are increased in the somatosensory cortex, and mGlu1 receptor expression is decreased in the thalamus. The two group I mGlu receptor-positive allosteric modulators (PAMs) VU0360172 and RO0711401 have an interesting profile in acute and (sub)chronic pharmacological studies and produce a dose-dependent decrease of SWDs. Moreover, both compounds are effective in reducing SWDs in the cortex and thalamus. Interestingly, the GABA reuptake blocker tiagabine reduces SWDs in the cortex and not in the thalamus, while the efficacy of ethosuximide is higher in the cortex than in the thalamus. It is thought that VU0360172 stimulates cortex GABA interneurons, which inhibit highly excitable cortical neurons in the focal area. In the thalamus, VU0360172 most likely reduces tonic inhibition. Thus, group I mGlu receptor PAMs might be further developed as anti-absence drugs, with putative disease-modifying effects on epileptogenesis. The preclinical profile of group I mGlu receptor PAMS deserves to be further explored in models of generalized epilepsy and focal types of epilepsy