Ralf W. Dittmann

Nonpharmacological interventions for ADHD: systematic review and meta-analyses of randomized controlled trials of dietary and psychological treatments

OBJECTIVE Nonpharmacological treatments are available for attention deficit hyperactivity disorder (ADHD), although their efficacy remains uncertain. The authors undertook meta-analyses of the efficacy of dietary (restricted elimination diets, artificial food color exclusions, and free fatty acid supplementation) and psychological (cognitive training, neurofeedback, and behavioral interventions) ADHD treatments. METHOD Using a common systematic search and a rigorous coding and data extraction strategy across domains, the authors searched electronic databases to identify published randomized controlled trials that involved individuals who were diagnosed with ADHD (or who met a validated cutoff on a recognized rating scale) and that included an ADHD outcome. RESULTS Fifty-four of the 2,904 nonduplicate screened records were included in the analyses. Two different analyses were performed. When the outcome measure was based on ADHD assessments by raters closest to the therapeutic setting, all dietary (standardized mean differences=0.21-0.48) and psychological (standardized mean differences=0.40-0.64) treatments produced statistically significant effects. However, when the best probably blinded assessment was employed, effects remained significant for free fatty acid supplementation (standardized mean difference=0.16) and artificial food color exclusion (standardized mean difference=0.42) but were substantially attenuated to nonsignificant levels for other treatments. CONCLUSIONS Free fatty acid supplementation produced small but significant reductions in ADHD symptoms even with probably blinded assessments, although the clinical significance of these effects remains to be determined. Artificial food color exclusion produced larger effects but often in individuals selected for food sensitivities. Better evidence for efficacy from blinded assessments is required for behavioral interventions, neurofeedback, cognitive training, and restricted elimination diets before they can be supported as treatments for core ADHD symptoms.

Atomoxetine and Methylphenidate Treatment in Children With ADHD: A Prospective, Randomized, Open-Label Trial

ABSTRACT Objective To assess the comparability of atomoxetine, a new therapy for attention-deficit/hyperactivity disorder (ADHD) and methylphenidate. (Atomoxetine was originally called tomoxetine. The name was recently changed in order to avoid any potential confusion with tamoxifen that might lead to errors in dispensing drug.) Method Children with ADHD were randomized to open-label atomoxetine or methylphenidate for 10 weeks. Response was assessed with the ADHD-IV Rating Scale. Results Two hundred twenty-eight patients were randomized (atomoxetine n = 184, methylphenidate n = 44). Both drugs were associated with marked improvement in inattentive and hyperactive-impulsive symptom clusters as assessed by parents and investigators. No statistically significant differences between treatment groups were observed on the primary outcome measure (investigator-rated ADHD-IV Rating Scale total score: atomoxetine baseline: 39.4 [8.5], endpoint: 20.0 [13.9]; methylphenidate baseline: 37.6 [9.7], endpoint: 19.8 (16.6); p = .66). Safety and tolerability were also similar between the 2 drugs. Discontinuations due to adverse events were 10/184 (5.4%) for atomoxetine and 5/44 (11.4%) for methylphenidate; p = .175. Conclusion These data provide preliminary evidence that atomoxetine is associated with therapeutic effects comparable to those of methylphenidate.

European guidelines on managing adverse effects of medication for ADHD

The safety of ADHD medications is not fully known. Concerns have arisen about both a lack of contemporary-standard information about medications first licensed several decades ago, and signals of possible harm arising from more recently developed medications. These relate to both relatively minor adverse effects and extremely serious issues such as sudden cardiac death and suicidality. A guidelines group of the European Network for Hyperkinetic Disorders (EUNETHYDIS) has therefore reviewed the literature, recruited renowned clinical subspecialists and consulted as a group to examine these concerns. Some of the effects examined appeared to be minimal in impact or difficult to distinguish from risk to untreated populations. However, several areas require further study to allow a more precise understanding of these risks.

Predictors and clinical consequences of non-adherence with antipsychotic medication in the outpatient treatment of schizophrenia

To assess baseline predictors and consequences of antipsychotic adherence during the long-term treatment of schizophrenia outpatients, data were taken from the 3-year, prospective, observational, European Schizophrenia Outpatients Health Outcomes (SOHO) study, in which outpatients starting or changing antipsychotics were assessed every 6 months. Physician-rated adherence was dichotomized as adherence/non-adherence. Regression models tested for predictors of adherence during follow-up, and associations between adherence and outcome measures. Of the 6731 patients analysed, 71.2% were adherent and 28.8% were non-adherent over 3 years. The strongest predictor of adherence was adherence in the month before baseline assessment. Other baseline predictors of adherence included initial treatment for schizophrenia and greater social activities. Baseline predictors of non-adherence were alcohol dependence and substance abuse in the previous month, hospitalization in the previous 6 months, independent housing and the presence of hostility. Non-adherence was significantly associated with an increased risk of relapse, hospitalization and suicide attempts. In conclusion, non-adherence is common but can partly be predicted. This may allow strategies to improve adherence to be targeted to high-risk patients. Also, reversal of some risk factors may improve adherence. Non-adherence is associated with a range of poorer long-term outcomes, with clinical and economic implications.

Cognitive Training for Attention-Deficit/Hyperactivity Disorder: Meta-Analysis of Clinical and Neuropsychological Outcomes From Randomized Controlled Trials

Objective The authors performed meta-analyses of randomized controlled trials to examine the effects of cognitive training on attention-deficit/hyperactivity disorder (ADHD) symptoms, neuropsychological deficits, and academic skills in children/adolescents with ADHD. Method The authors searched Pubmed, Ovid, Web of Science, ERIC, and CINAHAL databases through May 18, 2014. Data were aggregated using random-effects models. Studies were evaluated with the Cochrane risk of bias tool. Results Sixteen of 695 nonduplicate records were analyzed (759 children with ADHD). When all types of training were considered together, there were significant effects on total ADHD (standardized mean difference [SMD] = 0.37, 95% CI = 0.09–0.66) and inattentive symptoms (SMD = 0.47, 95% CI = 0.14–0.80) for reports by raters most proximal to the treatment setting (i.e., typically unblinded). These figures decreased substantially when the outcomes were provided by probably blinded raters (ADHD total: SMD = 0.20, 95% CI = 0.01–0.40; inattention: SMD = 0.32, 95% CI = −0.01 to 0.66). Effects on hyperactivity/impulsivity symptoms were not significant. There were significant effects on laboratory tests of working memory (verbal: SMD = 0.52, 95% CI = 0.24–0.80; visual: SMD = 0.47, 95% CI = 0.23–0.70) and parent ratings of executive function (SMD = 0.35, 95% CI = 0.08–0.61). Effects on academic performance were not statistically significant. There were no effects of working memory training, specifically on ADHD symptoms. Interventions targeting multiple neuropsychological deficits had large effects on ADHD symptoms rated by most proximal assessors (SMD = 0.79, 95% CI = 0.46–1.12). Conclusion Despite improving working memory performance, cognitive training had limited effects on ADHD symptoms according to assessments based on blinded measures. Approaches targeting multiple neuropsychological processes may optimize the transfer of effects from cognitive deficits to clinical symptoms.

Practitioner Review: Current Best Practice in the Management of Adverse Events during Treatment with ADHD Medications in Children and Adolescents.

BACKGROUND Medication is an important element of therapeutic strategies for ADHD. While medications for ADHD are generally well-tolerated, there are common, although less severe, as well as rare but severe adverse events AEs during treatment with ADHD drugs. The aim of this review is to provide evidence- and expert-based guidance concerning the management of (AEs) with medications for ADHD. METHODS For ease of use by practitioners and clinicians, the article is organized in a simple question and answer format regarding the prevalence and management of the most common AEs. Answers were based on empirical evidence from studies (preferably meta-analyses or systematic reviews) retrieved in PubMed, Ovid, EMBASE and Web of Knowledge through 30 June 2012. When no empirical evidence was available, expert consensus of the members of the European ADHD Guidelines Group is provided. The evidence-level of the management recommendations was based on the SIGN grading system. RESULTS The review covers monitoring and management strategies of loss of appetite and growth delay, cardiovascular risks, sleep disturbance, tics, substance misuse/abuse, seizures, suicidal thoughts/behaviours and psychotic symptoms. CONCLUSION Most AEs during treatment with drugs for ADHD are manageable and most of the times it is not necessary to stop medication, so that patients with ADHD may continue to benefit from the effectiveness of pharmacological treatment.

Non-stimulant medications in the treatment of ADHD.

AbstractBackgroundStimulants are the first–line medication in the psychopharmacological treatment of attention–deficit hyperactivity disorder (ADHD). However, 10 to 30% of all children and adults with ADHD either do not respond to or do not tolerate treatment with stimulants.ObjectiveTo describe alternative treatment approaches with various non–stimulant agents, especially atomoxetine.MethodGeneral review of empirically based literature concerning efficacy and safety of the substances.ResultsA large and still increasing body of data supports the usefulness of atomoxetine, a once daily dosing, and new selective noradrenalin reuptake inhibitor, with few side effects. Atomoxetine has been licensed in the US for use in ADHD across the lifespan, and is currently under consideration in Europe. Other non–stimulant substances, such as tricyclic antidepressants (TCAs) and alpha–2–adrenergic agonists, which are used to treat ADHD, are also reviewed. TCAs have been well studied and shown to be efficacious in the treatment of ADHD, but are limited by side effects. The number of studies documenting the efficacy of alpha–2–adrenergic agonists is still limited. Some experimental studies support a potential role of cholinergic drugs such as acetylcholinesterase inhibitors (tacrine, donepezil) as well as novel nicotinic analogues (ABT–418).ConclusionNon–stimulant agents have been shown to be effective in treatment of ADHD. Especially, atomoxetine seems promising and newline drugs are in development.

Olanzapine versus Placebo in Adolescents with Schizophrenia; a 6-Week, Randomized Double-Blind, Placebo-Controlled Trial.

OBJECTIVE To assess olanzapines efficacy and tolerability in adolescents with schizophrenia. METHOD One hundred seven inpatient and outpatient adolescents (olanzapine, n = 72, mean age 16.1 years; placebo, n = 35, mean age 16.3 years) with schizophrenia participated in this randomized (2:1), international, multisite, industry-sponsored trial. All patients met DSM-IV-TR criteria for schizophrenia, and they were treated for up to 6 weeks with flexible doses of olanzapine (2.5-20.0 mg/day) or placebo. Last-observation-carried-forward mean changes from baseline to endpoint on the anchored version of the Brief Psychiatric Rating Scale for Children, Clinical Global Impression Scale-Severity of Illness, and Positive and Negative Syndrome Scale (PANSS) were assessed. RESULTS More olanzapine-treated versus placebo-treated patients completed the trial (68.1% versus 42.9%, p =.020). Compared with placebo-treated patients, olanzapine-treated adolescents had significantly greater improvement in Brief Psychiatric Rating Scale for Children total (p =.003), Clinical Global Impressions Scale-Severity of Illness (p =.004), PANSS total (p =.005), and PANSS positive scores (p =.002). Olanzapine-treated patients gained significantly more baseline-to-endpoint weight (4.3 kg versus 0.1 kg, p <.001). Significantly more olanzapine-treated versus placebo-treated patients gained 7% or greater of their body weight at any time during treatment (45.8% versus 14.7%, p =.002). Prolactin and triglyceride mean baseline-to-endpoint changes were significantly higher in olanzapine-treated versus placebo-treated adolescents. The incidence of treatment-emergent significant changes in fasting glucose, cholesterol, or triglycerides did not differ between the groups at endpoint, but significantly more olanzapine-treated patients had high triglycerides at any time during treatment. CONCLUSIONS Olanzapine-treated adolescents with schizophrenia experienced significant symptom improvement. Significant increases in weight, triglycerides, uric acid, most liver function tests, and prolactin were observed during olanzapine treatment.Clinical trial registration information-Olanzapine Versus Placebo in the Treatment of Adolescents With Schizophrenia. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00051298.

Rates and predictors of remission and recovery during 3 years in 392 never-treated patients with schizophrenia

Objective:  Few studies have prospectively examined remission and recovery as well as their predictors in schizophrenia simultaneously. Aims of the study were to identify remission and recovery rates as well as their predictors in schizophrenia.

Clozapine and olanzapine are associated with food craving and binge eating: results from a randomized double-blind study.

The second generation antipsychotics clozapine and olanzapine frequently induce weight gain. Randomized studies investigating abnormal eating behavior (food craving, binge eating) possibly associated with weight gain are lacking. Thirty patients with schizophrenia, schizophreniform, or schizoaffective disorder were included in this randomized, double-blind, parallel study comparing abnormal eating behavior using a standardized scale, clinical efficacy using the Brief Psychiatric Rating Scale0-6 and Clinical Global Impression-Severity scale, and tolerability of clozapine and olanzapine. In both treatment groups, the number of patients reporting food craving, binge eating, or both increased over time. The likelihood to experience food craving at any time during drug treatment showed a trend (P = 0.068) to be higher in the olanzapine group (48.9%) compared with the clozapine group (23.3%). The likelihood to experience binge eating at any time during drug treatment was numerically but not statistically significantly higher in the olanzapine group (16.7%) than in the clozapine group (8.9%). In both groups, significant baseline-to-end point improvements of clinical symptoms (Brief Psychiatric Rating Scale0-6: clozapine, 36.6 ± 8.8 to 15.9 ± 13.7; olanzapine, 36.7 ± 9.9 to 19.1 ± 13.8) and severity of illness (Clinical Global Impression-Severity scale: clozapine, 4.7 ± 0.6 to 2.5 ± 1.5; olanzapine, 4.5 ± 0.6 to 2.3 ± 1.2) were observed. These improvements did not differ significantly between groups. Olanzapine was more tolerable than clozapine; adverse events occurred significantly (P < 0.01) less frequently than in the clozapine group. These results suggest that both clozapine and olanzapine can induce food craving and binge eating, however, olanzapine possibly to a greater extent. Findings on clinical efficacy and safety are in accordance with previous reports.