A systematic review of the safety of lisdexamfetamine dimesylate

BACKGROUND: Here we review the safety and tolerability profile of lisdexamfetamine dimesylate (LDX), the first long-acting prodrug stimulant for the treatment of attention-deficit/hyperactivity disorder (ADHD). METHODS: A PubMed search was conducted for English-language articles published up to 16 September 2013 using the following search terms: (lisdexamfetamine OR lisdexamphetamine OR SPD489 OR Vyvanse OR Venvanse OR NRP104 NOT review [publication type]). RESULTS: In short-term, parallel-group, placebo-controlled, phase III trials, treatment-emergent adverse events (TEAEs) in children, adolescents, and adults receiving LDX were typical for those reported for stimulants in general. Decreased appetite was reported by 25-39 % of patients and insomnia by 11-19 %. The most frequently reported TEAEs in long-term studies were similar to those reported in the short-term trials. Most TEAEs were mild or moderate in severity. Literature relating to four specific safety concerns associated with stimulant medications was evaluated in detail in patients receiving LDX. Gains in weight, height, and body mass index were smaller in children and adolescents receiving LDX than in placebo controls or untreated norms. Insomnia was a frequently reported TEAE in patients with ADHD of all ages receiving LDX, although the available data indicated no overall worsening of sleep quality in adults. Post-marketing survey data suggest that the rate of non-medical use of LDX was lower than that for short-acting stimulants and lower than or equivalent to long-acting stimulant formulations. Small mean increases were seen in blood pressure and pulse rate in patients receiving LDX. CONCLUSIONS: The safety and tolerability profile of LDX in individuals with ADHD is similar to that of other stimulants

Family-based clusters of cognitive test performance in familial schizophrenia

BACKGROUND: Cognitive traits derived from neuropsychological test data are considered to be potential endophenotypes of schizophrenia. Previously, these traits have been found to form a valid basis for clustering samples of schizophrenia patients into homogeneous subgroups. We set out to identify such clusters, but apart from previous studies, we included both schizophrenia patients and family members into the cluster analysis. The aim of the study was to detect family clusters with similar cognitive test performance. METHODS: Test scores from 54 randomly selected families comprising at least two siblings with schizophrenia spectrum disorders, and at least two unaffected family members were included in a complete-linkage cluster analysis with interactive data visualization. RESULTS: A well-performing, an impaired, and an intermediate family cluster emerged from the analysis. While the neuropsychological test scores differed significantly between the clusters, only minor differences were observed in the clinical variables. CONCLUSIONS: The visually aided clustering algorithm was successful in identifying family clusters comprising both schizophrenia patients and their relatives. The present classification method may serve as a basis for selecting phenotypically more homogeneous groups of families in subsequent genetic analyses

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries.

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors

The 5-HTTLPR polymorphism of the serotonin transporter gene and short term behavioral response to methylphenidate in children with ADHD

<p>Abstract</p> <p>Background</p> <p>Animal models of ADHD suggest that the paradoxical calming effect of methylphenidate on motor activity could be mediated through its action on serotonin transmission. In this study, we have investigated the relationship between the 5-HTTLPR polymorphism in the serotonin transporter gene (<it>SLC6A4</it>) and the response of ADHD relevant behaviors with methylphenidate treatment.</p> <p>Methods</p> <p>Patients between ages 6-12 (n = 157) were assessed with regard to their behavioral response to methylphenidate (0.5 mg/kg/day) using a 2-week prospective within-subject, placebo-controlled (crossover) trial. The children were then genotyped with regard to the triallelic 5-HTTLPR polymorphism in the <it>SLC6A4 </it>gene. Main outcome measure: Conners' Global Index for parents (CGI-Parents) and teachers (CGI-Teachers) at baseline and at the end of each week of treatment with placebo and methylphenidate. For both outcome measurements, we used a mixed model analysis of variance to determine gene, treatment and gene × treatment interaction effects.</p> <p>Results</p> <p>Mixed model analysis of variance revealed a gene × treatment interaction for CGI-Parents but not for CGI-Teachers. Children homozygous for the lower expressing alleles (<it>s+l_G= s'</it>) responded well to placebo and did not derive additional improvement with methylphenidate compared to children carrying a higher expressing allele (<it>l_A</it>). No genotype main effects on either CGI-Parents or CGI-teachers were observed.</p> <p>Conclusions</p> <p>A double blind placebo-controlled design was used to assess the behavioral effects of methylphenidate in relation to the triallelic 5-HTTLPR polymorphism of the <it>SLC6A4 </it>gene in children with ADHD. This polymorphism appears to modulate the behavioral response to methylphenidate in children with ADHD as assessed in the home environment by parents. Further investigation is needed to assess the clinical implications of this finding.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov NCT00483106</p

Speed, Variability, and Timing of Motor Output in ADHD: Which Measures are Useful for Endophenotypic Research?

Attention-Deficit/Hyperactivity Disorder (ADHD) shares a genetic basis with motor coordination problems and probably motor timing problems. In line with this, comparable problems in motor timing should be observed in first degree relatives and might, therefore, form a suitable endophenotypic candidate. This hypothesis was investigated in 238 ADHD-families (545 children) and 147 control-families (271 children). A motor timing task was administered, in which children had to produce a 1,000 ms interval. In addition to this task, two basic motor tasks were administered to examine speed and variability of motor output, when no timing component was required. Results indicated that variability in motor timing is a useful endophenotypic candidate: It was clearly associated with ADHD, it was also present in non-affected siblings, and it correlated within families. Accuracy (under- versus over-production) in motor timing appeared less useful: Even though accuracy was associated with ADHD (probands and affected siblings had a tendency to under-produce the 1,000 ms interval compared to controls), non-affected siblings did not differ from controls and sibling correlations were only marginally significant. Slow and variable motor output without timing component also appears present in ADHD, but not in non-affected siblings, suggesting these deficits not to be related to a familial vulnerability for ADHD. Deficits in motor timing could not be explained by deficits already present in basic motor output without a timing component. This suggests abnormalities in motor timing were predominantly related to deficient motor timing processes and not to general deficient motor functioning. The finding that deficits in motor timing run in ADHD-families suggests this to be a fruitful domain for further exploration in relation to the genetic underpinnings of ADHD

Effects of low birth weight, maternal smoking in pregnancy and social class on the phenotypic manifestation of Attention Deficit Hyperactivity Disorder and associated antisocial behaviour: investigation in a clinical sample

<p>Abstract</p> <p>Background</p> <p>Attention Deficit Hyperactivity Disorder (ADHD) is a genetically influenced condition although indicators of environmental risk including maternal smoking during pregnancy, low birth weight and low social class have also been found to be associated with the disorder.</p> <p>ADHD is a phenotypically heterogeneous disorder in terms of the predominant symptom types (inattention, hyperactive-impulsivity), their severity and comorbidity, notably Conduct Disorder. It is possible that these different clinical manifestations of the disorder may arise because of the differing effects of the environmental indicators of environmental risk. We set out to test this hypothesis.</p> <p>Methods</p> <p>In a sample of 356 children diagnosed with ADHD, we sought to investigate possible effects of three indicators of environmental risk – maternal smoking during pregnancy, birth weight and social class – on comorbid Conduct Disorder, conduct disorder symptoms and inattentive and hyperactive-impulsive symptom severity.</p> <p>Results</p> <p>Multiple regression analysis revealed that, after controlling for significant covariates, greater hyperactive-impulsive symptom severity was significantly associated with maternal smoking during pregnancy (r²= 0.02, Beta = 0.11, t = 1.96, p = 0.05) and social class (r²= 0.02, Beta = 0.12, t = 2.19, p = 0.03) whilst none of the environmental risk indicators significantly predicted number of inattentive symptoms. Conduct Disorder symptoms were positively predicted by maternal smoking in pregnancy (r²= 0.04, Beta = 0.18, t = 3.34, p = 0.001) whilst both maternal smoking during pregnancy and social class significantly predicted a diagnosis of Conduct Disorder (OR = 3.14, 95% CI: 1.54, 6.41, Wald = 9.95, p = 0.002) and (OR = 1.95 95% CI: 1.18, 3.23 Wald = 6.78, p = 0.009) respectively.</p> <p>Conclusion</p> <p>These findings suggest that indicators of environmental risk, in this instance maternal smoking in pregnancy and environmental adversity indexed by lower social class, independently influence the clinical presentation of the ADHD phenotype. Other types of study design are needed to investigate whether these associations between indicators of environmental risk factors and ADHD clinical heterogeneity are attributable to causal risk effects and to further establish the magnitude of these effects. These findings have implications, not only for our understanding of the aetiology of ADHD, but may also be of clinical value, enabling the identification of individuals who are at higher risk of problematic behaviours in ADHD, notably conduct disorder, to enable earlier, targeted risk reduction strategies.</p

The 'antisocial' person: an insight in to biology, classification and current evidence on treatment

<p>Abstract</p> <p>Background</p> <p>This review analyses and summarises the recent advances in understanding the neurobiology of violence and empathy, taxonomical issues on defining personality disorders characterised by disregard for social norms, evidence for efficacy of different treatment modalities and ethical implications in defining 'at-risk' individuals for preventive interventions.</p> <p>Methods</p> <p>PubMed was searched with the keywords 'antisocial personality disorder', 'dissocial personality disorder' and 'psychopathy'. The search was limited to articles published in English over the last 10 years (1999 to 2009)</p> <p>Results</p> <p>Both diagnostic manuals used in modern psychiatry, the <it>Diagnostic and Statistical Manual </it>published by the American Psychiatric Association and the <it>International Classification of Diseases </it>published by the World Health Organization, identify a personality disorder sharing similar traits. It is termed antisocial personality disorder in the diagnostic and statistical manual and dissocial personality disorder in the <it>International Classification of Diseases</it>. However, some authors query the ability of the existing manuals to identify a special category termed 'psychopathy', which in their opinion deserves special attention. On treatment-related issues, many psychological and behavioural therapies have shown success rates ranging from 25% to 62% in different cohorts. Multisystemic therapy and cognitive behaviour therapy have been proven efficacious in many trials. There is no substantial evidence for the efficacy of pharmacological therapy. Currently, the emphasis is on early identification and prevention of antisocial behaviour despite the ethical implications of defining at-risk children.</p> <p>Conclusions</p> <p>Further research is needed in the areas of neuroendocrinological associations of violent behaviour, taxonomic existence of psychopathy and efficacy of treatment modalities.</p

Potential biological role of poly (ADP-ribose) polymerase (PARP) in male gametes

Maintaining the integrity of sperm DNA is vital to reproduction and male fertility. Sperm contain a number of molecules and pathways for the repair of base excision, base mismatches and DNA strand breaks. The presence of Poly (ADP-ribose) polymerase (PARP), a DNA repair enzyme, and its homologues has recently been shown in male germ cells, specifically during stage VII of spermatogenesis. High PARP expression has been reported in mature spermatozoa and in proven fertile men. Whenever there are strand breaks in sperm DNA due to oxidative stress, chromatin remodeling or cell death, PARP is activated. However, the cleavage of PARP by caspase-3 inactivates it and inhibits PARP's DNA-repairing abilities. Therefore, cleaved PARP (cPARP) may be considered a marker of apoptosis. The presence of higher levels of cPARP in sperm of infertile men adds a new proof for the correlation between apoptosis and male infertility. This review describes the possible biological significance of PARP in mammalian cells with the focus on male reproduction. The review elaborates on the role played by PARP during spermatogenesis, sperm maturation in ejaculated spermatozoa and the potential role of PARP as new marker of sperm damage. PARP could provide new strategies to preserve fertility in cancer patients subjected to genotoxic stresses and may be a key to better male reproductive health

Examining the role of genetic risk and longitudinal transmission processes underlying maternal parenting and psychopathology and children’s ADHD symptoms and aggression: utilizing the advantages of a prospective adoption design

Although genetic factors may contribute to initial liability for ADHD onset, there is growing evidence of the potential importance of the rearing environment on the developmental course of ADHD symptomatology. However, associations between family-level variables (maternal hostility, maternal depressive symptoms) and child behaviors (developmental course of ADHD and aggression) may be explained by genes that are shared by biologically related parents and children. Furthermore, ADHD symptoms and aggression commonly co-occur: it is important to consider both simultaneously to have a better understanding of processes underlying the developmental course of ADHD and aggression. To addresses these issues, we employed a longitudinal genetically sensitive parent–offspring adoption design. Analyses were conducted using Cohort I (n = 340) of the Early Growth and Development Study with cross-validation analyses conducted with Cohort II (n = 178). Adoptive mother hostility, but not depression, was associated with later child ADHD symptoms and aggression. Mothers and their adopted children were genetically unrelated, removing passive rGE as a possible explanation. Early child impulsivity/activation was associated with later ADHD symptoms and aggression. Child impulsivity/activation was also associated with maternal hostility, with some evidence for evocative gene-environment correlation processes on adoptive mother depressive symptoms. This study provides novel insights into family-based environmental influences on child ADHD and aggression symptoms, independent of shared parental genetic factors, implications of which are further explicated in the discussion