Current Pharmaceutical Design

ISSN: 1381-6128

Current Pharmaceutical Design
Volume 16, Number 22, 2010

Contents

Psychotropic Drugs in Child and Adolescent Psychiatry - a New Era on the Horizon
Executive Editors: Aribert Rothenberger, Manfred Gerlach and Ralf W. Dittmann


Editorial Pp. 2395-2397


Safeguarding Children’s Rights in Psychopharmacological Research: Ethical and Legal Issues Pp. 2398-2406
Michael Kölch, Andrea G. Ludolph, Paul L. Plener, Heiner Fangerau, Benedetto Vitiello and Joerg M. Fegert
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Randomized Clinical Trials in Children - Ethical and Methodological Issues Pp. 2407-2415
Andreas D. Henschel, Lillian G. Rothenberger and Joachim Boos
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Improving Medication Adherence in Chronic Pediatric Health Conditions: A Focus on ADHD in Youth Pp. 2416-2423
Anil Chacko, Jeffrey H. Newcorn, Nicole Feirsen and Jodi Z. Uderman
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Stimulant Drug Effects on Attention Deficit/Hyperactivity Disorder: A Review of the Effects of Age and Sex of Patients Pp. 2424-2433
Christine Cornforth, Edmund Sonuga-Barke and David Coghill
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What can Actigraphy Add to the Concept of Labschool Design in Clinical Trials? Pp. 2434-2442
Henrik Uebel, Björn Albrecht, Roumen Kirov, Alexander Heise, Manfred Döpfner, Franz Joseph Freisleder, Wolff Dieter Gerber, Michael Günter, Frank Hässler, Claudia Ose, Fritz Poustka, Roland Fischer, Tobias Banaschewski and Aribert Rothenberger
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The Pharmaceutical Economics of Child Psychiatric Drug Treatment Pp. 2443-2461
Michael Schlander
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Pharmacogenetic Approach for a Better Drug Treatment in Children Pp. 2462-2473
Guilherme Polanczyk, Marcelo P. Bigarella, Mara H. Hutz and Luis Augusto Rohde
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Postnatal Brain Development and Psychotropic Drugs. Effects on Animals and Animal Models of Depression and Attention Deficit/Hyperactivity Disorder Pp. 2474-2483
Nathalie Bock, Manfred Gerlach and Aribert Rothenberger
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General Articles


Novel and Current Treatment Concepts Using Pulmonary Drug Delivery Pp. 2484-2492
Martin Hohenegger
[Abstract] [Purchase Article]


Targeting the p53 Pathway of Apoptosis Pp. 2493-2503
Joana D. Amaral, Joana M. Xavier, Clifford J. Steer and Cecília M.P. Rodrigues
[Abstract] [Purchase Article]



Abstracts


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Safeguarding Children’s Rights in Psychopharmacological Research: Ethical and Legal Issues
Michael Kölch, Andrea G. Ludolph, Paul L. Plener, Heiner Fangerau, Benedetto Vitiello and Joerg M. Fegert

Objective: Research on psychopharmacological treatment in children and adolescents is the subject of ongoing ethical discussion, as minors with mental disorders constitute a vulnerable patient group. Considering the important legislative changes in pediatric research over the past decade in both the US and Western Europe, there is a need to review recent developments in this area.

Method: Based on a systematic literature review, a hermeneutical analysis focusing the main issues of ethics in child and adolescent psychopharmacology is provided. Legal and regulatory aspects of psychopharmacological research in children are compared between the US and Europe. Relevant issues were informed assent and consent to research participation, minimal risk and burden of research, ethics of pharmacogenetics, research on “me-too” medications, and justice in global research. Additionally, the concern about undue influence of financial interests in research is also addressed.

Conclusion: Incentives for the conduct of clinical trials with children comparable to those contained in US legislation are now provided in the EU. Research to develop “me-too” preparations may have no significant benefit for children, but can cause research burden and detract from clinically more important projects by utilizing limited investigator time and patient resources. Thus far, pharmacogenetic studies may bring more individualized treatment approaches into child psychiatry but they remain at present a promise for the future. Finally, the issues of avoiding undue influence from funders and conflicts of interest remain a prominent concern which can be solved by declaring conflicts and publishing all results of studies extensively.


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Randomized Clinical Trials in Children - Ethical and Methodological Issues
Andreas D. Henschel, Lillian G. Rothenberger and Joachim Boos

Randomization is an internationally accepted methodological tool used to perform sound clinical research. To ensure the clinical value of medical interventions, both evidence based medicine and new drug approvals require that randomized controlled trials (RCT) be conducted. Randomization prevents the manipulation of participant allocation and balances unknown confounders in a way no other method can. The gold standard RCT, however, is complex to conduct and requires significant financial and structural resources. In consequence, drug development and registration are primarily driven by the pharmaceutical industry. Within the field of pediatrics, we need high quality research tailored to children in order to reduce off-label use and to ensure that we expose children only to effective and, above all, safe drug treatments. The American and European regulatory authorities now offer programs to support such studies and clinical researchers and pharmaceutical industries are obliged to put them into practice in the best interest of the children. Issues relating to feasibility as well as ethical issues must be born in mind when planning RCTs in child populations. Obtaining informed assent from children in an adequate manner is one of several key elements. Moreover, it is essential to ensure equipoise before conducting a trial. Thus, issues relating to acceptability can be addressed and the discrimination of treatment groups within RCTs can be prevented.

This narrative review addresses ethical and methodological aspects of RCTs in adults and especially in children and includes a quantitative analysis, which explores issues relating to the publication of RCTs.


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Improving Medication Adherence in Chronic Pediatric Health Conditions: A Focus on ADHD in Youth
Anil Chacko, Jeffrey H. Newcorn, Nicole Feirsen and Jodi Z. Uderman

Chronic pediatric health conditions pose a significant challenge for youth, their families and professionals who treat these conditions. Long-term adherence to interventions, including and often-times, pharmacological interventions, is necessary but often problematic. Understanding factors related to poor adherence and intervening to improve adherence is essential in order to maximize long-term outcomes. Attention-deficit/hyperactivity disorder (ADHD) is one such chronic health condition requiring long-term adherence to treatment. The aims of this review are to 1) review the extant literature regarding rates of adherence to medication for youth with ADHD; 2) summarize what is known regarding factors that impede and support greater adherence to medication; 3) introduce the Unified Theory of Behavior Change as a conceptual model that may assist in developing adherence treatment packages to support medication adherence; and 4) describe several potential interventions based on the Unified Theory of Behavior Change that may improve adherence to medication for youth with ADHD. Although pharmacological interventions for youth with ADHD have been evaluated for decades, only more recently has adherence to medication been the subject of interest. However, this literature has exclusively focused on understanding factors related to adherence, with no empirical studies of interventions to improve adherence in youth with ADHD. This paper provides a rationale and research agenda for systematic study of interventions to support medication adherence in youth with ADHD.


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Stimulant Drug Effects on Attention Deficit/Hyperactivity Disorder: A Review of the Effects of Age and Sex of Patients
Christine Cornforth, Edmund Sonuga-Barke and David Coghill

Objective: As dopamine functioning varies by sex and age it might be expected that the effects of methylphenidate or amfetamine, the psychostimulants used for the treatment of Attention Deficit /Hyperactivity Disorder (ADHD), will also be moderated by these factors. Here we review the published literature on whether stimulant effects in ADHD symptoms vary by age and sex.

Method: We searched for studies published from 1989 until October 2009. Databases searched included U.S. National Library of Medicine (PubMed), Medline, EMBASE, PsycINFO and ISI Web of Knowledge. Firstly, we reviewed the effects of stimulant drugs on male and female patients and also patients of pre-school, middle childhood, adolescence and adulthood. Secondly, we reviewed studies that directly tested the moderating effect of age and sex on stimulant treatment outcome.

Results: Randomised controlled trials confirm that stimulant medication is efficacious for, and well tolerated by, males and females and patients across the age range; although preschoolers appear to have a less beneficial response and more side effects. Few studies that specifically examined the moderating effect of age and/or sex were identified. For sex, no effects on overall response were found, although one study reported that sex moderated methylphenidate pharmacodynamics. The few effects found for age were small and inconsistent.

Conclusions: The available evidence suggests that stimulant medication, when appropriately administered, has efficacy as an ADHD treatment for both sexes and across all ages. There are currently too few published papers examining the effects of sex and age to draw strong conclusions about moderation. Further studies of the pharmacodynamics of stimulants on symptoms measured using objective tests in the laboratory or classroom setting need to be undertaken.


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What can Actigraphy Add to the Concept of Labschool Design in Clinical Trials?
Henrik Uebel, Björn Albrecht, Roumen Kirov, Alexander Heise, Manfred Döpfner, Franz Joseph Freisleder, Wolff Dieter Gerber, Michael Günter, Frank Hässler, Claudia Ose, Fritz Poustka, Roland Fischer, Tobias Banaschewski and Aribert Rothenberger

Pharmacological intervention with methylphenidate (MPH) is very common and helpful in the treatment of attention-deficit/hyperactivity disorder (ADHD). It ameliorates inattention, impulsivity and hyperactivity and improves psychosocial functioning. The core symptoms of ADHD are problematic mainly in demanding structured situations such as in the classroom. It was argued that MPH does not only lead to a decrease of hyperactivity in these situations but may also result in a general dampening of motor activity during non-structured leisure time. Unfortunately, only few clinical trials have investigated this practically important issue and thus it is still a matter of debate. It follows that many parents hesitate to accept psychotropic drugs for their children. To elucidate this problem in the current study, not only overall behavioral ratings (half-day blocks) but also day-long actigraphy was applied during an analogue classroom setting, where structured and non-structured situations alternated over time. Fourty-nine children with ADHD were assessed for treatment effects of once-daily extended-release and twice daily immediate-release methylphenidate (MPH) as well as placebo.

Both MPH regimes yielded improved behavioral ratings during morning and afternoon, while actigraphy showed reduced motor activity in structured situations, but not during leisure time. Furthermore, the movement information obtained with actigraphy during structured situations could be differentiated from the one gained with overall behavioral ratings.

Thus, while behavioral ratings provide a valid estimate of the overall symptomatology, additional information gathered with actigraphy may help to differentiate the impact of medication on hyperactive movement in different situations during the day. This may reflect a more valid picture of a child’s real life and improve the quality of clinical trials. Thus, both methods may be regarded as complementary for the assessment of drug effects in children with ADHD and should be a standard of further laboratory school protocols in clinical trials.


This review highlights several important aspects related to the design and statistical analysis for pharmacogenomics studies or clinical trials, which incorporate biomarkers. First, we review biomarker development: how biomarkers may be used as targets and the difference between prognostic and predictive markers. Second, in confirmatory clinical trials, we focus on issues related to study design for evaluating biomarkers and how they can be used to determine which patients might optimally benefit from a specific therapy. Finally, we review exploratory statistical screening techniques for detecting biomarkers in Phase I or pharmacokinetics studies.

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The Pharmaceutical Economics of Child Psychiatric Drug Treatment
Michael Schlander

Over the last decade, the number of health economic evaluations has increased substantially in the field of child psychiatry. The objective of the present paper is to offer an overview of economic evaluations of child psychiatric drug treatment. Major electronic databases, as well as abstract booklets from international clinical and health economics conferences with an external peer review process, were examined to search for comparative economic evaluations of child and adolescent psychiatric drug treatment. Most studies of pharmacotreatment were cost effectiveness analyses (CEAs) concerned with attention-deficit/hyperactivity disorder (ADHD). Three evaluations were done by or on behalf of agencies as part of ADHD-related health technology assessments. A number of economic studies used patient-level data from specific randomized clinical trials, especially the NIMH-initiated MTA (in childhood ADHD) and TADS (in adolescent major depression) studies. Almost all studies relied on narrow scale symptom scales to assess effects of treatment, even when quality-adjusted life years (QALYs) were reported. In many cases, effectiveness data came from short-term studies, and extrapolation to a one-year time horizon was usually based on assumptions. Even those evaluations attempting to address longer time horizons by way of modeling did not include the impact of treatment on long-term sequelae of the conditions studied, mainly due to a paucity of robust clinical data. Nevertheless, currently available health economic evaluations broadly suggest an acceptable to attractive cost effectiveness of medication management of ADHD, whereas there is no such evidence for child psychiatric disorders other than ADHD.


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Pharmacogenetic Approach for a Better Drug Treatment in Children
Guilherme Polanczyk, Marcelo P. Bigarella, Mara H. Hutz and Luis Augusto Rohde

Objective: We conducted a systematic review of the literature aiming to identify original studies that have evaluated the effect of genes on the response to medications used to treat psychiatric disorders in children and adolescents.

Results: We included 35 original studies on the pharmacogenetics of childhood psychiatric disorders. Thirty-three studies addressed the association between genes, particularly dopamine transporter gene (DAT1) and dopamine D4 receptor gene (DRD4), and response to medication for the treatment of attention-deficit/hyperactivity disorder (ADHD). Only two studies investigated atomoxetine as the pharmacological intervention, and the other 31 studies investigated methylphenidate (MPH). One study assessed children with depression and anxiety disorders and another assessed children with autism; in both of them selective serotonin reuptake inhibitors (SSRIs) were the pharmacological intervention.

Conclusion: The existing literature on the pharmacogenetics of ADHD suggests that response to MPH is influenced by several different polymorphisms, each one exerting a small effect. Genome-wide association studies and multi-center collaborative projects are likely to overcome the barriers for the development of the field. Future investigations should evaluate, besides improvement of symptoms, emergence of clinically relevant side effects. The lessons we have learned from the progress of the pharmacogenetics of ADHD can be relevant for developing pharmacogenetic studies in other child and adolescent psychiatric disorders.



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Postnatal Brain Development and Psychotropic Drugs. Effects on Animals and Animal Models of Depression and Attention Deficit/Hyperactivity Disorder
Nathalie Bock, Manfred Gerlach and Aribert Rothenberger

In recent years an increased use of psychotropic medication in children has been observed, but little is known about the influence of this medication on brain maturation. Probably, because of methodological problems and/or ethical aspects. It means that only naturalistic observational studies might allow to get some insight in humans. But even animal studies touching this issue are scarce and heterogeneous. Nevertheless, postnatal brain development is highly sensitive to the effects of psychotropic drugs, either in the short- and/or long-term. Therefore, more and better information is needed. The main targets of psychotropic drugs are the monoaminergic transmitter systems that are related to brain networks for motor behavior, motivation, emotion, and cognition. In order to elucidate the mechanisms of drug development interactions and their long-term consequences on brain and behavior, animal studies might provide a good basis for a better understanding and guidance of research in humans. Hence, this article reviews the possible influence of those psychotropic drugs on postnatal brain development in animals (mostly rats and rodents) which are widely used to treat common psychiatric disorders in children and adolescents like depression and attention-deficit/hyperactivity disorder (ADHD). Moreover this review refers to the obvious problems of the available animal studies (including experimental animal models of child psychiatric disorders) which seem to be of limited value in translating experimental knowledge to the complexity of clinical understanding and practice.


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Novel and Current Treatment Concepts Using Pulmonary Drug Delivery
Martin Hohenegger

The novel technologies in pulmonary drug delivery propelled the development of new strategies for pharmacological intervention in human diseases. In particular, this review will focus on pulmonary parameters which influence the delivery of inhaled therapeutics and summarize novel applications and recent innovations. The central issues of pulmonary drug application are optimal effectiveness under conditions of greatest safety. They not only depend on the properties of the drug but also feature the application vehicle and drug formulation. The optimization of the whole system (drug, formulation and vehicle) is therefore a necessary prerequisite for reliable inhaling medicines. Depending on the desired locus of drug action, the inhaled medicine has to be adjusted to particle size, concentration and chemical composition to guarantee a local or systemic drug action. Local asthma therapy represents the established concept for inhalation therapy. Due to the disease status, deposition of drugs is therefore often seen in central rather than peripheral airways. Recent developments in ultrafine therapeutic particles should therefore provide enough drug deposition even in the deeper airways. Recent approvals and interesting new therapy concepts will be discussed. Beside a pulmonary drug action there is an accumulating number of applications also for systemic drug action after pulmonary drug delivery. These involve among others inhaled insulin, glucagon-like-peptide 1 or growth hormone. But also novel therapeutic systems for gene therapy and vaccination are currently under investigation. Successful feasibility of these novel concepts will be expected in the near future.


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Targeting the p53 Pathway of Apoptosis
Joana D. Amaral, Joana M. Xavier, Clifford J. Steer and Cecília M.P. Rodrigues

The tumor suppressor protein, p53 is regarded as a key player in tumor suppression, as it promotes growth arrest, apoptosis and cellular senescence, while also blocking angiogenesis. The plethora of mechanisms underlying the p53 efficient death response involves transcriptional activation or repression of target genes, as well as the recently identified microRNAs, and transcription-independent functions. Pathological conditions such as cancer, neurodegeneration, ischemia, cholestasis or atherosclerosis are all strongly associated with deregulated levels of apoptosis in which p53 dysfunction has a prominent role. The effect of targeting cell death signaling proteins has been established in preclinical models of human diseases. In this regard, therapeutic strategies aimed at reactivation of p53 in tumors emerge as a promising approach for the treatment of cancer patients, as well as chemical inhibitors of p53 that may prove effective in suppressing disorders associated with widespread p53 activation. This review highlights recent developments of p53-induced apoptosis in human diseases. In addition, we will discuss controversies arising from the double-edge sword of targeting p53 in disease. Finally, ursodeoxycholic acid (UDCA), an endogenous bile acid used to treat cholestatic liver diseases, was recently described as a fine modulator of the complex control of p53 by Mdm-2. We will also review recent therapeutic strategies and clinical applications of targeted agents, and their progress in drug lead discovery, with particular emphasis on the potential use of UDCA.