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1.  Suicide related events and attention deficit hyperactivity disorder treatments in children and adolescents: a meta-analysis of atomoxetine and methylphenidate comparator clinical trials 
Attention Deficit Hyperactivity Disorder (ADHD) is becoming an increasingly commonly diagnosed and treated childhood illness. Untreated ADHD is recognised as an independent risk factor for suicide-related events and deliberate self-harm and is reported more commonly in these populations. With the treatment of ADHD it is thus crucial to understand further any associations between pharmacological treatments and suicide-related events. Specific data for suicide-related events with stimulants have not been publically reported. Suicidal tendencies are, however, a contraindication to the treatment of patients with methylphenidate. Clinicians and patients may be helped by a meta-analytic comparison of suicide-related events in comparative randomised double-blind atomoxetine and methylphenidate clinical trials.
Suicide-related events retrospectively mapped to the suicide-related event assessment instrument recommended by the FDA, the Columbia Classification Algorithm for Suicide Assessment (C-CASA), were evaluated in five double-blind placebo controlled comparative studies of atomoxetine and methylphenidate (n = 1024) of 6 to 9 weeks duration. The Mantel-Haenszel risk ratio and Mantel-Haenszel incidence differences have been calculated.
In total there were 5 suicide-related events, atomoxetine (ATX) 3/559 and methylphenidate (MPH) 2/465. There were no suicide attempts nor completed suicides. Meta-analysis finds no difference of a difference in risk between ATX and MPH with a Mantel-Haenszel risk ratio of 0.52 (95% CI; 0.06, 4.54).
In the only reported meta-analysis of comparative suicide-related events between atomoxetine and methylphenidate, no significant evidence of a difference in risk has been found. These data may be informative to clinicians and patients when developing clinical guidelines.
PMCID: PMC3691607  PMID: 23777626
ADHD; Suicide-related events; Summary of product characteristics; Systematic review; Atomoxetine; Methylphenidate
2.  A 12-week nursing support programme for carers of children and adolescents in the UK with attention deficit hyperactivity disorder prescribed atomoxetine 
Patient support programmes are assuming greater importance in the UK in many therapeutic areas, mostly with the aim of improving adherence to medication and many being provided by the pharmaceutical industry. Atomoxetine is a noradrenaline reuptake inhibitor for the treatment of attention deficit hyperactivity disorder that has recently demonstrated incremental efficacy for at least 12 weeks. Issues of adherence may be predicted over this initial period particularly if adverse events are reported. The Strattera Support Service was initiated in 2006 ( funded by Eli Lilly) to provide advice, initially through telephone contact, by trained nurses during the first 12 weeks of atomoxetine therapy and is offered to carers of patients diagnosed with ADHD after atomoxetine has been prescribed. The aim of this pilot service evaluation is to assess discontinuation rates and compare them with historical control data.
Data from patients in the service who initiated atomoxetine between 1 January 2009 and 31 March 2010 were analysed to provide a pilot service evaluation. Continuation rates of patients in the service who were taking atomoxetine at week 12 were assessed and compared with historical control data.
Between 1 January 2009 and 31 March 2010, 346 patients (300 male patients) enrolled in the programme and commenced treatment with atomoxetine. The mean age of patients was 10.5 years. At 12 weeks, 33 (9.5%) patients had discontinued treatment; continuation rates were similar regardless of age and sex. Discontinuation rates of 39% are reported from historical control data.
Preliminary data from a 12-week atomoxetine patient support programme are supportive that discontinuation rates may be lower than historically expected. Further service evaluations of this programme may be required.
PMCID: PMC3805395  PMID: 24167677
ADHD; atomoxetine; Strattera support service; adherence; discontinuation rates
3.  Electrophysiological Cross-Language Neighborhood Density Effects in Late and Early English-Welsh Bilinguals 
Behavioral studies with proficient late bilinguals have revealed the existence of orthographic neighborhood density (ND) effects across languages when participants read either in their first (L1) or second (L2) language. Words with many cross-language (CL) neighbors have been found to elicit more negative event-related potentials (ERPs) than words with few CL neighbors (Midgley et al., 2008); the effect started earlier, and was larger, for L2 words. Here, 14 late and 14 early English-Welsh bilinguals performed a semantic categorization task on English and Welsh words presented in separate blocks. The pattern of CL activation was different for the two groups of bilinguals. In late bilinguals, words with high CLND elicited more negative ERP amplitudes than words with low CLND starting around 175 ms after word onset and lasting until 500 ms. This effect interacted with language in the 300–500 ms time window. A more complex pattern of early effects was revealed in early bilinguals and there were no effects in the N400 window. These results suggest that CL activation of orthographic neighbors is highly sensitive to the bilinguals’ learning experience of the two languages.
PMCID: PMC3475346  PMID: 23087661
bilingualism; ERPs; neighborhood density; reading; orthography
4.  A systematic review of the safety information contained within the Summaries of Product Characteristics of medications licensed in the United Kingdom for Attention Deficit Hyperactivity Disorder. how does the safety prescribing advice compare with national guidance? 
The safety of paediatric medications is paramount and contraindications provide clear pragmatic advice. Further advice may be accessed through Summaries of Product Characteristics (SPCs) and relevant national guidelines. The SPC can be considered the ultimate independent guideline and is regularly updated. In 2008, the authors undertook a systematic review of the SPC contraindications of medications licensed in the United Kingdom (UK) for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). At that time, there were fewer contraindications reported in the SPC for atomoxetine than methylphenidate and the specific contraindications varied considerably amongst methylphenidate formulations. In 2009, the European Medicines Agency (EMA) mandated harmonisation of methylphenidate SPCs. Between September and November 2011, there were three changes to the atomoxetine SPC that resulted in revised prescribing information. In addition, Clinical Guidance has also been produced by the National Institute for Health and Clinical Excellence (NICE) (2008), the Scottish Intercollegiate Guidelines Network (SIGN) (2009) and the British National Formulary for Children (BNFC).
An updated systematic review of the Contraindications sections of the SPCs of all medications currently licensed for treatment of ADHD in the UK was undertaken and independent statements regarding contraindications and relevant warnings and precautions were then compared with UK national guidance with the aim of assessing any disparity and potential areas of confusion for prescribers.
As of November 2011, there were seven medications available in the UK for the treatment of ADHD. There are 15 contraindications for most formulations of methylphenidate, 14 for dexamfetamine and 5 for atomoxetine. Significant differences exist between the SPCs and national guidance part due to the ongoing reactive process of amending the former as new information becomes known. In addition, recommendations are made outside UK SPC licensed indications and a significant contraindication for methylphenidate (suicidal behaviours) is missing from both the NICE and SIGN guidelines. Particular disparity exists relating to monitoring for suicidal and psychiatric side effects. The BNFC has not yet been updated in line with the European Union (EU) Directive on methylphenidate; it does not include any contraindications for atomoxetine but describes contraindications for methylphenidate that are no longer in the SPC.
Clinicians seeking prescribing advice from critical independent sources of data, such as SPCs and national guidelines, may be confused by the disparity that exists. There are major differences between guidelines and SPCs and neither should be referred to in isolation. The SPC represents the most relevant source of safety data to aid prescribing of medications for ADHD as they present the most current safety data in line with increased exposure. National guidelines may need more regular updates.
PMCID: PMC3317854  PMID: 22234242
ADHD; guidelines; summary of product characteristics; drug safety; NICE; SIGN
5.  Atomoxetine in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder. Systematic Review of Review Papers 2009–2011. An Update for Clinicians 
Attention deficit/hyperactivity disorder (ADHD) is a common disorder and a plethora of new data has been published from clinical trials and national epidemiological databases in the last three years. In the United Kingdom Atomoxetine is currently the only licensed non-stimulant medication. As part of a systematic review of atomoxetine data Jan 2009–June 2011 formal searches found 750 citations. From these 13 met criteria for either review or systematic review papers and contained clinical data synthesis on atomoxetine. No individual review paper alone would be sufficient for clinicians to be updated at that time on all clinical aspects of atomoxetine data. The crucial data relating to clinical parity of atomoxetine and methylphenidate in trials and meta-analysis where relevant confounding biases are removed are not often discussed. Systematic review of complex data is critical for ADHD clinicians and will need regular updating due to the large volume of new data.
PMCID: PMC3663616  PMID: 23861650
ADHD; suicidality; summary of product characteristics; systematic review; review; atomoxetine
6.  Electrophysiological Evidence for Impaired Attentional Engagement with Phonologically Acceptable Misspellings in Developmental Dyslexia 
Event-related potential (ERP) studies of word recognition have provided fundamental insights into the time-course and stages of visual and auditory word form processing in reading. Here, we used ERPs to track the time-course of phonological processing in dyslexic adults and matched controls. Participants engaged in semantic judgments of visually presented high-cloze probability sentences ending either with (a) their best completion word, (b) a homophone of the best completion, (c) a pseudohomophone of the best completion, or (d) an unrelated word, to examine the interplay of phonological and orthographic processing in reading and the stage(s) of processing affected in developmental dyslexia. Early ERP peaks (N1, P2, N2) were modulated in amplitude similarly in the two groups of participants. However, dyslexic readers failed to show the P3a modulation seen in control participants for unexpected homophones and pseudohomophones (i.e., sentence completions that are acceptable phonologically but are misspelt). Furthermore, P3a amplitudes significantly correlated with reaction times in each experimental condition. Our results showed no sign of a deficit in accessing phonological representations during reading, since sentence primes yielded phonological priming effects that did not differ between participant groups in the early phases of processing. On the other hand, we report new evidence for a deficient attentional engagement with orthographically unexpected but phonologically expected words in dyslexia, irrespective of task focus on orthography or phonology. In our view, this result is consistent with deficiency in reading occurring from the point at which attention is oriented to phonological analysis, which may underlie broader difficulties in sublexical decoding.
PMCID: PMC3124829  PMID: 21734903
developmental dyslexia; event-related potential; P3a; attention; orthographic processing; homophone; reading
7.  Differences between children and adolescents in treatment response to atomoxetine and the correlation between health-related quality of life and Attention Deficit/Hyperactivity Disorder core symptoms: Meta-analysis of five atomoxetine trials 
To explore the influence of age on treatment responses to atomoxetine and to assess the relationship between core symptoms of attention deficit/hyperactivity disorder (ADHD) and health-related quality of life (HR-QoL) outcomes.
Data Sources
Data from five similar clinical trials of atomoxetine in the treatment of children and adolescents with ADHD were included in this meta-analysis.
Study Selection
Atomoxetine studies that used the ADHD Rating Scale (ADHD-RS) and the Child Health and Illness Profile Child Edition (CHIP-CE) as outcome measures were selected.
Treatment with atomoxetine.
Main Outcome Measures
Treatment group differences (atomoxetine vs placebo) in terms of total score, domains, and subdomains of the CHIP-CE were compared across age groups, and correlations between ADHD-RS scores and CHIP-CE scores were calculated by age.
Data of 794 subjects (611 children, 183 adolescents) were pooled. At baseline, adolescents showed significantly (p < 0.05) greater impairment compared with children in the Family Involvement, Satisfaction with Self, and Academic Performance subdomains of the CHIP-CE. Treatment effect of atomoxetine was significant in both age groups for the Risk Avoidance domain and its subdomains. There was a significant age-treatment interaction with greater efficacy seen in adolescents in both the Risk Avoidance domain and the Threats to Achievement subdomain. Correlations between ADHD-RS and CHIP-CE scores were generally low at baseline and moderate in change from baseline and were overall similar in adolescents and children.
Atomoxetine was effective in improving some aspects of HR-QoL in both age groups. Correlations between core symptoms of ADHD and HR-QoL were low to moderate.
PMCID: PMC3012018  PMID: 21134277

Results 1-7 (7)