Mats Johnson

Computerized Training of Working Memory in Children With ADHD-A Randomized, Controlled Trial

OBJECTIVE Deficits in executive functioning, including working memory (WM) deficits, have been suggested to be important in attention-deficit/hyperactivity disorder (ADHD). During 2002 to 2003, the authors conducted a multicenter, randomized, controlled, double-blind trial to investigate the effect of improving WM by computerized, systematic practice of WM tasks. METHOD Included in the trial were 53 children with ADHD (9 girls; 15 of 53 inattentive subtype), aged 7 to 12 years, without stimulant medication. The compliance criterion (>20 days of training) was met by 44 subjects, 42 of whom were also evaluated at follow-up 3 months later. Participants were randomly assigned to use either the treatment computer program for training WM or a comparison program. The main outcome measure was the span-board task, a visuospatial WM task that was not part of the training program. RESULTS For the span-board task, there was a significant treatment effect both post-intervention and at follow-up. In addition, there were significant effects for secondary outcome tasks measuring verbal WM, response inhibition, and complex reasoning. Parent ratings showed significant reduction in symptoms of inattention and hyperactivity/impulsivity, both post-intervention and at follow-up. CONCLUSIONS This study shows that WM can be improved by training in children with ADHD. This training also improved response inhibition and reasoning and resulted in a reduction of the parent-rated inattentive symptoms of ADHD.

Co-existing disorders in ADHD - implications for diagnosis and intervention

Abstract.BackgroundIt is only recently that “comorbidity” in ADHD has come to the forefront as one of the most important aspects of the disorder. It is agreed that, often, these problems are at least as important as ADHD in contributing to the longer term outcome in the individual child.ObjectiveTo provide the reader with basic information about clinics and treatment of “comorbidity” in ADHD.MethodReview of the empirically based literature.ResultsADHD exists in a surprisingly high frequency together with a broad range of child neuropsychiatric disorders. This is accompanied with many still unresolved treatment problems.ConclusionIt would not be appropriate to develop ADHD–services where clinicians would only have expertise in ADHD as such. Anyone working with children, adolescents and adults with ADHD would need to have training in general neuropsychiatry. Further research in this field is urgently needed.

Omega-3/Omega-6 Fatty Acids for Attention Deficit Hyperactivity Disorder A Randomized Placebo-Controlled Trial in Children and Adolescents

Objective: The aim of the study was to assess omega 3/6 fatty acids (eye q) in attention deficit hyperactivity disorder (ADHD). Method: The study included a randomized, 3-month, omega 3/6 placebo-controlled, one-way crossover trial with 75 children and adolescents (8—18 years), followed by 3 months with omega 3/6 for all. Investigator-rated ADHD Rating Scale—IV and Clinical Global Impression (CGI) scale were outcome measures. Results: A majority did not respond to omega 3/6 treatment. However, a subgroup of 26% responded with more than 25% reduction of ADHD symptoms and a drop of CGI scores to the near-normal range. After 6 months, 47% of all showed such improvement. Responders tended to have ADHD inattentive subtype and comorbid neurodevelopmental disorders. Conclusion: A subgroup of children and adolescents with ADHD, characterized by inattention and associated neurodevelopmental disorders, treated with omega 3/6 fatty acids for 6 months responded with meaningful reduction of ADHD symptoms. (J. of Att. Dis. 2009; 12(5) 394-401)

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.

Comorbid oppositional defiant disorder and the risk of relapse during 9 months of atomoxetine treatment for attention- deficit/hyperactivity disorder

ObjectiveTo examine the influence of comorbid oppositional defiant disorder (ODD) on the relative risk (RR) of relapse during 9 months of treatment with atomoxetine for attention-deficit/hyperactivity disorder (ADHD).MethodFour hundred and sixteen children and adolescents with ADHD whose symptoms remitted during initial 10-week, open-label atomoxetine treatment were randomly assigned to continue with atomoxetine or placebo.ResultsIn all, 43% met criteria for comorbid ODD. A total of 17% of patients with comorbid ODD relapsed (CGI-Severity score ≥ 3 and ADHD Rating Scale total score of 90% or more of baseline at study entry on two consecutive visits) during atomoxetine treatment, compared with 26% of patients without comorbid ODD (RR 0.67, 95% CI 0.42–1.06). Mean time to relapse was not significantly different [mean (SE) days to relapse, ADHD/ +ODD: 215 (7.38); ADHD/–ODD: 211 (7.61); log rank p=0.08]. This finding is placed within the context of atomoxetine affording an overall protection against relapse compared with placebo (RR 0.59, 95% CI 0.43–0.80).ConclusionsComorbid ODD does not influence the rate of relapse of patients with ADHD during longer-term treatment with atomoxetine. Atomoxetine protects against the relapse of ADHD symptoms regardless of the presence or absence of comorbid ODD.

A prospective, multicenter, open-label assessment of atomoxetine in non-North American children and adolescents with ADHD.

Abstract.Objective:The aim of this study was to study treatment response to atomoxetine in a large, multicenter study of non-North American patients with ADHD.Methods:A total of 604 children and adolescents with ADHD were enrolled in a 10-week open-label trial with atomoxetine prior to randomization to a double-blind relapse prevention phase at 33 sites in the United Kingdom, continental Europe, Israel, South Africa, and Australia. All patients had ADHD symptom severity at least 1.5 standard deviations above United States age and gender norms for their diagnostic subtype as measured by the investigator-scored ADHD Rating Scale (ADHD RS). Outcomes were assessed by analysis of change in the ADHD RS; functional and psychosocial outcomes were assessed using the Child Health Questionnaire (CHQ).Results:At endpoint, ADHD RS total scores decreased by an average of 56.7%, and 69% of patients were rated as having no or minimal symptoms. Significant improvement was observed in psychosocial and functional outcomes. Discontinuations attributed to adverse events were < 4%.Conclusion:These open-label data, gathered in an international setting, add to our knowledge of the value of atomoxetine in treating ADHD symptoms, as well as its safety and tolerability.

Maintenance of Efficacy of Lisdexamfetamine Dimesylate in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder: Randomized-Withdrawal Study Design

OBJECTIVE In this phase 3 extension study, the long-term maintenance of efficacy of lisdexamfetamine dimesylate (LDX) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) was evaluated using a randomized-withdrawal study design. METHOD European and US patients (6-17 years; N = 276) with ADHD were entered into a 26-week open-label trial of LDX treatment. Those who completed the open-label period (n = 157) were randomized 1:1 to their optimized dose of LDX (30, 50, or 70 mg per day) or placebo for a 6-week randomized-withdrawal period (RWP). The primary efficacy measure was the proportion of patients meeting treatment failure criteria (≥50% increase in ADHD Rating Scale IV total score and ≥2-point increase in Clinical Global Impressions-Severity of Illness [CGI-S] score, compared with RWP start point). Safety and tolerability were also evaluated. RESULTS During the RWP (LDX, n = 78; placebo, n = 79), significantly fewer patients receiving LDX met treatment failure criteria (15.8%) compared with those receiving placebo (67.5%; difference = -51.7%; 95% confidence interval = -65.0, -38.5; p < .001 ). Most treatment failures occurred at or before the week 2 visit after randomization. Treatment-emergent adverse events were reported in 39.7% and 25.3% of patients receiving LDX and placebo, respectively, during the RWP. CONCLUSIONS These data demonstrate the maintenance of efficacy of LDX during long-term treatment in children and adolescents with ADHD. The rapid return of symptoms on LDX withdrawal demonstrates the need for continuing treatment. The safety profile of LDX was consistent with that of other stimulants. Clinical trial registration information-Double-Blind, Placebo-Controlled, Randomized Withdrawal, Extension, Safety and Efficacy Study of LDX in Children and Adolescents Aged 6-17; http://clinicaltrials.gov; NCT00784654.

Lisdexamfetamine dimesylate: a new therapeutic option for attention-deficit hyperactivity disorder.

Attention-deficit hyperactivity disorder (ADHD) is associated with substantial functional, clinical and economic burdens. It is among the most common psychiatric disorders in children and adolescents, and often persists into adulthood. Both medication and psychosocial interventions are recommended for the treatment of ADHD. However, ADHD treatment practices vary considerably, depending on medication availability, reimbursement and the evolution of clinical practice in each country. In Europe, stimulants and atomoxetine are widely available medications for the treatment of ADHD, whereas in the US approved treatment options also include extended-release formulations of clonidine and guanfacine. Lisdexamfetamine dimesylate (lisdexamfetamine) is a long-acting, prodrug formulation of dexamfetamine. It is currently licensed in the US, Canada and Brazil, and is undergoing phase III studies in Europe. We performed a PubMed/MEDLINE search looking for recent (2005–2012) scientific papers regarding the pharmacokinetics, pharmacodynamics, efficacy and safety of lisdexamfetamine. The lisdexamfetamine molecule is therapeutically inactive and is enzymatically hydrolysed, primarily in the blood, to the active dexamfetamine. This conversion is unaffected by gastrointestinal pH and variations in normal transit times. Lisdexamfetamine was developed with the goal of providing an extended duration of effect that is consistent throughout the day. Clinical trials have demonstrated robust clinical efficacy of lisdexamfetamine in the treatment of children, adolescents and adults with ADHD with dose-dependent improvements in the core symptoms of ADHD. Studies have further shown that the duration of action of lisdexamfetamine continues for 13 hours post-dosing in children and for 14 hours in adults. The tolerability profile of lisdexamfetamine is consistent with those of other stimulant medications, with decreased appetite, insomnia, abdominal pain and irritability among the more frequent treatment-emergent adverse events, most of which are mild to moderate in intensity and transient in nature. There are currently no parallel-group, head-to-head trial data comparing the efficacy and safety of lisdexamfetamine with other medications for ADHD. However, the available data, including a large effect size and consistent plasma concentrations throughout the day, suggest that lisdexamfetamine is a useful treatment option for patients with ADHD.

Open-label trial of atomoxetine hydrochloride in adults with ADHD.

Background: While atomoxetine is an established treatment for attention-deficit/hyperactivity disorder in children, few studies have examined its efficacy for adults. Methods: Open-label trial of atomoxetine in 20 individuals with ADHD, aged 19-47 years, for 10 weeks, and a total of one year for responders. Results: Ten patients met primary efficacy criteria at 10 weeks. Only one patient completed the whole study. Six patients discontinued before 10 weeks and thirteen at 10 weeks or later, mainly because of side-effects (aggression, depressed mood, raised liver enzymes, thyroid hormones, diastolic blood pressure), decreasing efficacy or non-compliance. Conclusion: Fifty percent responded to treatment, but only one patient (5%) felt sufficient improvement to continue for one year. Dosage may have been too low, and baseline impairment too high, for atomoxetine to have sufficient effect on ADHD symptoms in our group of adults. The majority had few side-effects, but several terminated treatment because of adverse effects.

Chronology of Greece and South-east Europe in the Final Neolithic and Early Bronze Age.

Final Neolithic to Early Bronze Age chronology in Greece remains obscure due to a lack of stratified deposits and radiocarbon dates. In this paper the Greek evidence is considered in the light of typological parallels, stratigraphic sequences, and the larger series of radiocarbon dates available from the south-east European cultures, and a tentative chronology for Greece and south-east Europe is presented. The evidence does not support the earlier notion of an overlap between the Thessalian Rachmani period and the Early Helladic period of southern Greece, but rather suggests that Rachmani is essentially contemporary with the southern Greek Final Neolithic. The Final Neolithic–Early Bronze Age transition in southern Greece shows affinities to Petromagoula in Thessaly and the Boleraz culture of Europe. Several radiocarbon dates place the Boleraz period in the early 5th millennium BP, suggesting that dates from FN–EBA transitional contexts in Greece may, in the future, help to fill the existing early 5th millennium gap in the Greek radiocarbon date series.