Alexander Schacht

Social and emotional impairment in children and adolescents with ADHD and the impact on quality of life.

This review provides an overview as to how the social and emotional impairments involved in Attention-Deficit/Hyperactivity Disorder affect the quality of life of patients and their families. A model of three categories into which the emotional difficulties fall, and how they impair quality of life, is also presented.

Duloxetine and pregabalin: High-dose monotherapy or their combination? The ''COMBO-DN study'' - a multinational, randomized, double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain

Summary Combination of the standard doses of duloxetine and pregabalin was not superior to the maximum dose of either drug in patients with painful diabetic neuropathy. Abstract This multicentre, double‐blind, parallel‐group study in diabetic peripheral neuropathic pain addressed whether, in patients not responding to standard doses of duloxetine or pregabalin, combining both medications is superior to increasing each drug to its maximum recommended dose. For initial 8‐week therapy, either 60 mg/day duloxetine (groups 1, 2) or 300 mg/day pregabalin (groups 3, 4) was given. Thereafter, in the 8‐week combination/high‐dose therapy period, only nonresponders received 120 mg/day duloxetine (group 1), a combination of 60 mg/day duloxetine and 300 mg/day pregabalin (groups 2, 3), or 600 mg/day pregabalin (group 4). Primary outcome (Brief Pain Inventory Modified Short Form [BPI‐MSF] 24‐hour average pain change after combination/high‐dose therapy) was analyzed comparing combination (groups 2, 3 pooled) with high‐dose monotherapy (groups 1, 4 pooled). Secondary end points included response rates, BPI‐MSF severity items, and comparison of duloxetine and pregabalin in BPI‐MSF average pain. Eight hundred four patients were evaluated for initial therapy and 339 for combination/high‐dose therapy. There were no significant differences between combination and high‐dose monotherapy regarding BPI‐MSF average pain (mean change: combination: −2.35; high‐dose monotherapy: −2.16; P = 0.370) and most secondary end points, which, however, consistently favoured combination therapy. Fifty‐percent response rates were 52.1% for combination and 39.3% for high‐dose monotherapy (P = 0.068). In exploratory analyses of the initial 8‐week therapy uncorrected for multiple comparisons, 60 mg/day duloxetine was found superior to 300 mg/day pregabalin (P < 0.001). Both drugs and their combination were well tolerated. Although not significantly superior to high‐dose monotherapy, combination therapy was considered to be effective, safe, and well tolerated.

A Randomized Double-Blind Study of Atomoxetine versus Placebo for Attention-Deficit/Hyperactivity Disorder Symptoms in Children with Autism Spectrum Disorder.

OBJECTIVE The efficacy of atomoxetine as treatment of symptoms of attention-deficit/hyperactivity disorder (ADHD) in patients with autism spectrum disorder (ASD) has not been established. METHOD In this study, 97 patients aged 6 to 17 years with ADHD and ASD were randomly assigned to double-blind treatment with 1.2 mg/kg/day atomoxetine or placebo for 8 weeks. The primary endpoint was the ADHD Rating Scale (ADHD-RS) score; secondary endpoints were the Clinical Global Impression of ADHD-Improvement (CGI-I) and the Conners Teacher Rating Scale-Revised: Short Form (CTRS-R:S) score. RESULTS Baseline mean ADHD-RS scores for atomoxetine versus placebo were 40.7 and 38.6; after 8 weeks, mixed-effect model repeated-measure means were 31.6 (95% confidence interval 29.2-33.9) and 38.3 (36.0-40.6), respectively, with a difference in least square means of -6.7 (-10.0 to -3.4; p < .001). The CTRS-R:S Hyperactivity subscore also improved significantly for atomoxetine compared with placebo, but not the other CTRS-R:S subscores. However, there were not significantly more patients on atomoxetine (20.9%) who improved much, or very much according to the CGI-I, than on placebo (8.7%; p = 0.14). Adverse events (mostly nausea, decrease in appetite, fatigue, and early morning awakening) were reported in 81.3% of atomoxetine patients and 65.3% of placebo patients (p > .1). There were no serious adverse events. CONCLUSIONS Atomoxetine moderately improved ADHD symptoms in patients with ASD and was generally well tolerated. Adverse events in this study were similar to those in other studies with ADHD patients without ASD. Clinical trial registration information-A Randomized Double-Blind Study of Atomoxetine Versus Placebo for ADHD Symptoms in Children with ASD; www.clinicaltrials.gov; NCT00380692.

Neuropathic pain phenotyping as a predictor of treatment response in painful diabetic neuropathy: data from the randomized, double-blind, COMBO-DN study.

&NA; Duloxetine and pregabalin have different effects on neuropathic pain components. This might explain differential responses to these drugs when given either alone or in combination. &NA; Sensory profiles are heterogeneous in neuropathic pain disorders, and subgroups of patients respond differently to treatment. To further explore this, patients in the COMBO‐DN study were prospectively assessed by the Neuropathic Pain Symptom Inventory (NPSI) at baseline, after initial 8‐week therapy with either duloxetine or pregabalin, and after subsequent 8‐week combination/high‐dose therapy. Exploratory post hoc cluster analyses were performed to identify and characterize potential subgroups through their scores in the NPSI items. In patients not responding to initial 60 mg/d duloxetine, adding 300 mg/d pregabalin for combination treatment was particularly effective regarding the dimensions pressing pain and evoked pain, whereas maximizing the duloxetine dose to 120 mg/d appeared more beneficial regarding paresthesia/dysesthesia. In contrast, adding 60 mg/d duloxetine to 300 mg/d pregabalin in case of nonresponse to initial pregabalin led to numerically higher decreases in all NPSI dimensions/items compared to maximizing the pregabalin dose to 600 mg/d. Cluster analysis revealed 3 patient clusters (defined by baseline scores for the 10 NPSI sensory items) with different pain profiles, not only in terms of overall pain severity, but also across NPSI items. Mean Brief Pain Inventory average pain improved in all clusters during combination/high‐dose therapy. However, in patients with severe pain, the treatment effect showed a trend in favor of high‐dose monotherapy, whereas combination therapy appeared to be more beneficial in patients with moderate and mild pain (not significant). These complementary exploratory analyses further endorse the idea that sensory phenotyping might lead to a more stratified treatment and potentially to personalized pain therapy.

Neuropsychological Outcomes Across the Day in Children with Attention-Deficit/Hyperactivity Disorder Treated with Atomoxetine: Results from a Placebo-Controlled Study Using a Computer-Based Continuous Performance Test Combined with an Infra-Red Motion-tracking Device

The effect of atomoxetine (ATX) on executive function has been assessed by means of questionnaires only. The aim of this study was therefore to evaluate the efficacy of ATX using standard variables of a computer-based continuous performance test (cb-CPT) combined with an infra-red motion-tracking device at different times of the day. One hundred twenty-eight girls and boys aged 6 to 12 years with a diagnosis of ADHD according to DSM-IV-TR criteria were randomized in the study. The primary efficacy measures were the q-scores of the cb-CPT combined with an infra-red motion-tracking device. The test comprises 13 neuropsychological variables that can be taken to reflect hyperactivity, inattention, or impulsivity. One hundred five patients completed the study (ATX group: n=54; placebo group: n=51). ATX (target dose 1.2 mg/kg/day) over 8 weeks was significantly superior to placebo in reducing hyperactivity, inattention, and impulsivity as measured by q-scores of 10 primary variables of the cb-CPT. Both groups of patients showed a circadian pattern of neuropsychological outcomes across the day as reflected by the cb-CPT combined with an infra-red motion-tracking device. In summary, this study demonstrated a positive effect of ATX on some aspects of executive function, inhibitory control, and hyperactivity compared with placebo.

Long-term patterns of subjective wellbeing in schizophrenia: Cluster, predictors of cluster affiliation, and their relation to recovery criteria in 2842 patients followed over 3 years

OBJECTIVE To study the longitudinal patterns of subjective wellbeing in schizophrenia using cluster analysis and their relation to recovery criteria, further to examine predictors for cluster affiliation, and to evaluate the sensitivity and specificity of baseline subjective wellbeing cut-offs for cluster affiliation. METHODS Data was collected in an observational 36-month follow-up study of 2842 patients with schizophrenia in Germany. Subjective wellbeing was assessed using the SWN-K scale. Cluster analyses were applied based on Wards procedure. Predictors were analyzed using logistic regression models. Optimal SWN-K total score cut-off points for cluster affiliation were analyzed using Cohens kappa. RESULTS 4 distinct clusters were identified: a stable low (33%), a stable moderate (31%), a stable high (16%), and a cluster with distinct initial improvement and then stable high subjective wellbeing (20%). Highly concordant patterns were also observed for symptoms, social functioning, and quality of life. Sensitivity and specificity of SWN-K total score cut-offs at baseline were 82.8% and 63.8% for <or=60 points for the stable low cluster and 84.7% and 95.4% for >or=80 points for the stable high cluster. Affiliation to the stable low cluster was related to a 0.6% chance of being in recovery at 3-year endpoint. CONCLUSIONS Long-term patterns of subjective wellbeing are stable and highly concordant with course of symptoms, functioning level, and quality of life. Baseline subjective wellbeing cut-off points were found to be sufficient predictors of outcome, which, particularly in case of impaired subjective wellbeing and low baseline functioning level, make early treatment adaptations mandatory.

Atomoxetine versus placebo in children and adolescents with attention-deficit/hyperactivity disorder and comorbid oppositional defiant disorder: a double-blind, randomized, multicenter trial in Germany.

OBJECTIVES The primary objective of this study was to evaluate the efficacy of atomoxetine (ATX, target dose 1.2 mg/kg daily) on symptoms of oppositional defiant disorder (ODD) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). A secondary objective was to compare fast versus slow up-titration of ATX. METHODS This was a 3-arm, 9-week, randomized, placebo-controlled, double-blind study in ADHD patients (6-17 years) with comorbid ODD (Diagnostic and Statistical Manual of Mental Disorders, 4th edition [DSM-IV] criteria A-C) or conduct disorder (CD). ATX-treatment arms were as follows-ATX-fast: 7 days 0.5 mg/kg, then 1.2 mg/kg; ATX-slow: 7 days each at 0.5 and 0.8 mg/kg, then 1.2 mg/kg. Primary outcome was the Swanson, Nolan, and Pelham Rating Scale-Revised (SNAP-IV) ODD-score after 9 weeks (Mixed Effects Model for Repeated Measures, ATX-up-titration groups pooled). RESULTS In total, 181 patients were randomized, and 180 evaluated (ATX-fast/ATX-slow/placebo: 60/61/59). Baseline characteristics were comparable (84.4% boys; mean age 11.0 years; DSM-IV: 100% ADHD, 75.6% with combined type, 74.4% ODD, 24.4% CD; SNAP-IV ODD-scores, mean ± standard deviation 15.5 ± 4.35). At week 9, SNAP-IV ODD scores were significantly lower versus placebo in both ATX-groups (least square mean [95% confidence interval]: ATX-fast 8.6 [7.2;9.9]; ATX-slow 9.0 [7.7;10.3]; placebo 12.0 [10.6;13.5]; least square mean, ATX-pooled minus placebo: -3.2 [-5.0, -1.5], effect size: -0.69, p < 0.001). SNAP-IV ADHD-scores, CD symptoms (investigator-rated Attention-Deficit and Disruptive Behavior Disorders Instrument, disruptive behavior), Clinical Global Impressions-Severity, and individual treatment behaviors showed corresponding results. Post-hoc analyses indicated interrelationships between the medication effects on ADHD, ODD, and CD symptom scores. For ATX-slow, time to early dropout was significantly longer versus placebo (Hazard Ratio [95% confidence interval]: 3.57 [1.42;8.94]; p = 0.007). Clinically relevant adverse effects (fatigue, sleep disorders, nausea, and gastrointestinal complaints; weeks 1-3) were reported in 60.0% of ATX-fast, 44.3% of ATX-slow, and 18.6% of placebo group patients. CONCLUSIONS ATX for 9 weeks significantly reduced symptoms of ODD/CD and ADHD; slower ATX-up-titration may be better tolerated.

Effectiveness of Atomoxetine and Quality of Life in Children with Attention-Deficit/Hyperactivity Disorder as Perceived by Patients, Parents, and Physicians in an Open-Label Study

OBJECTIVES Health-related quality of life in children with attention-deficit/hyperactivity disorder (ADHD) may improve with atomoxetine treatment. However, the degree of improvement may be perceived differently by patients, parents, and physicians. The primary aim of this study was to investigate ADHD-related difficulties as perceived from these three perspectives and to compare the perspectives. The degree of perceived difficulties was taken to reflect the health-related quality of life of patients in the study. A second objective was to assess the effectiveness of atomoxetine in children with ADHD in an open-label setting. METHODS Children aged 6-11 years with ADHD were treated for 24 weeks with atomoxetine at a target dose of 0.5-1.2 mg/kg per day. ADHD-related difficulties were assessed after 8 and 24 weeks of treatment using the newly devised Global Impression of Perceived Difficulties (GIPD) scale. This instrument, that has not yet been psychometrically validated, reflects patient quality of life from the three perspectives. Agreement among the perspectives was determined using Cohens kappa. RESULTS A total of 262 patients was treated with atomoxetine. The mean dose for the respective visit intervals ranged between 1.15 and 1.17 mg/kg per day. Quality of life as reflected by the degree of perceived difficulties improved over time. Change in GIPD scores was greatest within the first 2 weeks. The course of the mean GIPD total scores over time showed a similar pattern among the three different rater perspectives. However, patients perceived the degree of difficulties as significantly less compared to parents and physicians. Agreement of ratings was highest between physicians and parents. CONCLUSIONS Results from the GIPD suggest that patient quality of life improves with time on atomoxetine. The effectiveness of atomoxetine in an open-label study was very similar to the effectiveness shown in placebo-controlled trials.

Global impression of perceived difficulties in children and adolescents with attention-deficit/hyperactivity disorder: Reliability and validity of a new instrument assessing perceived difficulties from a patient, parent and physician perspective over the day

BackgroundThe objective of this analysis was to evaluate the psychometric properties of a brief scale developed to assess the degree of difficulties in children with Attention-Deficit/Hyperactivity Disorder (ADHD). The Global Impression of Perceived Difficulties (GIPD) scale reflects overall impairment, psychosocial functioning and Quality of Life (QoL) as rated by patient, parents and physician at various times of the day.MethodsIn two open-label studies, ADHD-patients aged 6–17 years were treated with atomoxetine (target-dose 0.5–1.2 mg/kg/day). ADHD-related difficulties were assessed up to week 24 using the GIPD. Data from both studies were combined to validate the scale.ResultsOverall, 421 patients received atomoxetine. GIPD scores improved over time. All three GIPD-versions (patient, parent, physician) were internally consistent; all items showed at least moderate item-total correlation. The scale showed good test-retest reliability over a two-week period from all three perspectives. Good convergent and discriminant validity was shown.ConclusionGIPD is an internally consistent, reliable and valid measure to assess difficulties in children with ADHD at various times of the day and can be used as indicator for psychosocial impairment and QoL. The scale is sensitive to treatment-related change.

Change in the direct cost of treatment for children and adolescents with hyperkinetic disorder in Germany over a period of four years

BackgroundIn many developed countries, the treatment of hyperkinetic disorder (or ADHD) consumes a considerable amount of resources. The primary aim of this study was to determine change in the direct cost of treatment for children and adolescents with hyperkinetic disorder in Germany over time, and compare the cost with the cost of treatment for two physical disorders: epilepsy and asthma.MethodsThe German Federal Statistical Office provided data on the direct cost of treating hyperkinetic disorder, epilepsy and asthma in Germany for 2002, 2004, and 2006. The direct costs of treatment incurred by hyperkinetic disorder in these years were compared with those incurred by epilepsy and asthma.ResultsThe total direct cost of treatment for the hyperkinetic disorder was € 177 million in 2002, € 234 million in 2004, and € 341 million in 2006. The largest proportion of the cost was incurred by the age group < 15 years: € 158 million in 2002, € 205 million in 2004, and € 287 million in 2006. The direct cost of treatment for epilepsy in this age group was a total of € 157 million in 2002, € 155 million in 2004, and € 155 million in 2006. For asthma, the total direct cost of treatment in this age group was € 266 million in 2002, € 257 million in 2004, and € 272 million in 2006.ConclusionThe direct cost of treatment for hyperkinetic disorder in the age group < 15 years increased considerably between 2002 and 2006. Over the same period of time and for the same age group, expenditure for epilepsy and asthma was more or less constant. The increase in expenditure for the treatment of hyperkinetic disorder may be due to increasing demand for diagnostic and therapeutic services and improved availability of such services. The study is limited by the difficulty of obtaining consistent data on the direct cost of treatment for both physical and psychiatric disorders in Germany.