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European Neuropsychopharmacology (2015) 25, 15131531

http://dx.doi.org/10924-977X/& 2015 E

nCorresponding aufax: +39 6 22541195

E-mail address: a



Unmet needs in paediatricpsychopharmacology: Present scenarioand future perspectives

Antonio M. Persicoa,b,n, Celso Arangoc, Jan K. Buitelaard,Christoph U. Correlle, Jeffrey C. Glennond, Pieter J. Hoekstraf,Carmen Morenoc, Benedetto Vitiellog, Jacob Vorstmanh,Alessandro Zuddasi, the European Child and Adolescent ClinicalPsychopharmacology Networkj

aChild & Adolescent NeuroPsychiatry Unit, University Campus Bio-Medico, Rome, ItalybMafalda Luce Center for Pervasive Developmental Disorders, Milan, ItalycChild and Adolescent Psychiatry Department, Hospital General Universitario Gregorio Maran, School ofMedicine Universidad Complutense, IiSGM, CIBERSAM, Madrid, SpaindDepartment of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, RadboudUniversity Medical Centre, and Karakter Child and Adolescent Psychiatry University Centre, Nijmegen,The NetherlandsePsychiatry Research, The Zucker Hillside Hospital, North Shore-Long Island Jewish Health System, GlenOaks, NY, USAfDepartment of Psychiatry, University of Groningen, University Medical Center, Groningen, TheNetherlandsgNational Institute of Mental Health, Bethesda, MD, USAhDepartment of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, TheNetherlandsiDept. Biomedical Sciences, Child & Adolescent NeuroPsychiatry Unit, University of Cagliari, Cagliari, ItalyjThe European Child and Adolescent Clinical Psychopharmacology Network is a workgroup of the ECNPChild and Adolescent Neuropsychopharmacology Network; it currently consists of the following members:Celso Arango, Tobias Banaschewski (Mannheim, Germany), Jan K. Buitelaar, Josefina Castro-Fornieles(Barcelona, Spain), David Coghill (Dundee, UK), David Cohen (Paris, France), Ralf W. Dittmann (Mannheim,Germany), Jrg M. Fegert (Ulm, Germany), Pieter J. Hoekstra, Carmen Moreno, Antonio M. Persico, DianePurper Ouakil (Montpellier, France), Mara Parellada (Madrid, Spain), Veit Roessner (Dresden, Germany),Alessandro Zuddas

Received 8 February 2015; received in revised form 17 May 2015; accepted 12 June 2015

0.1016/j.euroneuro.2015.06.009lsevier B.V. and ECNP. All rights reserved.

thor at: Child & Adolescent NeuroPsychiatry Unit, University Campus Bio-Medico, Rome, Italy. Tel.: +39 6 225419155;6..persico@unicampus.it (A.M. Persico).


A.M. Persico et al.1514

KEYWORDSAutism spectrum dis-order;Biomarkers;Intellectual disability;Off-label use;Pharmaceutical poli-cies;Psychopharmacology

AbstractPaediatric psychopharmacology holds great promise in two equally important areas of enormousbiomedical and social impact, namely the treatment of behavioural abnormalities in childrenand adolescents, and the prevention of psychiatric disorders with adolescent- or adult-onset.Yet, in striking contrast, pharmacological treatment options presently available in child andadolescent psychiatry are dramatically limited. The most important currently unmet needs inpaediatric psychopharmacology are: the frequent off-label prescription of medications tochildren and adolescents based exclusively on data from randomized controlled studiesinvolving adult patients; the frequent lack of age-specific dose, long-term efficacy andtolerability/safety data; the lack of effective medications for many paediatric psychiatricdisorders, most critically autism spectrum disorder; the scarcity and limitations of randomizedplacebo-controlled trials in paediatric psychopharmacology; the unexplored potential for theprevention of psychiatric disorders with adolescent- and adult-onset; the current lack ofbiomarkers to predict treatment response and severe adverse effects; the need for betterpreclinical data to foster the successful development of novel drug therapies; and the effectivedissemination of evidence-based treatments to the general public, to better inform patientsand families of the benefits and risks of pharmacological interventions during development.Priorities and strategies are proposed to overcome some of these limitations, including theEuropean Child and Adolescent Clinical Psychopharmacology Network, as an overarching Pan-European infrastructure aimed at reliably carrying out much needed psychopharmacologicaltrials in children and adolescents, in order to fill the identified gaps and improve overalloutcomes.& 2015 Elsevier B.V. and ECNP. All rights reserved.

1. Introduction

All theoretical frameworks to describe and analyse psycho-logical functioning and human behaviour invariably viewchildhood and adolescence as crucial to the development oflife-long mental health and disease. In recent decades, thegrowth of basic neuroscience has indeed pushed develop-mental psychology beyond limited descriptions and inter-pretations of human cognitive, emotional and behaviouraltrajectories, into a bio-psycho-social framework where theneurobiological underpinnings of typical development hold akey position (Lee et al., 2014; Schumann et al., 2014).Within this framework, the link between abnormal neuro-development and paediatric psychopathology has becomethe object of intense investigation, which holds a realisticpromise to produce major advances in developmentalneuropsychopharmacology in the not-so-distant future.Furthermore, adult psychiatric disorders have been shownto at least partly stem from neurodevelopmental abnorm-alities arising from early or late childhood, if not evenprenatally (Salum et al., 2010).

Recognizing this great potential for major upcomingprogress in clinical practice, but also acknowledging theserious limitations of current psychopharmacologicalinterventions in paediatric neuropsychiatry, the Child &Adolescent Neuropsychopharmacology Network of theEuropean College of Neuropsychopharmacology (ECNP;http://www.ecnp.eu/) held a Targeted Network Meeting(TNM) on October 4, 2013, satellite to the 26th AnnualECNP Congress (Barcelona, Spain). Thirteen experts pre-sented evidence, shared opinions, described policies anddebated views around the many unmet needs in child

psychopharmacology. In the ensuing year, a dialogue onthese subjects was continued by the participants with thegoal of producing the present meeting report, whichprovides a snapshot of the most critical unmet needs,summarized in Table 1, as well as a general framework toguide future collaborative efforts and advance the field ofpaediatric psychopharmacology.

2. The off-label prescription to children andadolescents of medications with regulatoryapproval only in adults

Developmental neuropsychopharmacology has progressivelyevolved from considering youth as small adults, toinvestigating new fields of interest specific to children andadolescents (Arango, 2015). However, to date only very fewmedications have been approved in Europe for use inchildren and adolescents (Table 2). Many psychotropicmedications prescribed to paediatric patients are unli-censed and off-label. In fact, the vast majority of medicinesprescribed to children throughout the European Union (EU)have actually never been studied in this population but onlyin adults, and not necessarily for the same disease (Conroyet al. 2000). This unlicensed and off-label use conceivablystems from: (i) a dearth of clinical trials in paediatricpopulations, due to insufficient commercial incentivesand/or ethical barriers associated with studies in childrenand adolescents; (ii) delays in licensing medications foryouth, and (iii) lack of suitable formulations for paediatricpatients. On the one hand, regulatory authorities havedenied registration for the majority of these medications,due to the lack of extensive information on long-term

Table 1 Summary of the unmet needs in current child and adolescent neuropsychopharmacology and proposed solutions.

Unmet needs Proposed solutions

The frequent off-label prescription to children andadolescents of medications with regulatory approval onlyin adults

Insufficient long-term efficacy and safety information inthe paediatric population

Off-label prescriptions not always supported by sufficientevidence

Monitoring the efficacy of EU Regulations n. 1901/2006 and1902/2006 requiring a Paediatric Investigational Plan (PIP)for all newly marketed drugs, and of the 6-month patentextension granted by the FDA to pharmaceuticalcompanies providing long-term efficacy and safetyinformation for the paediatric population. The ultimategoal should be to promote more Paediatric Use MarketingAuthorizations (PUMAs)

Pharmacological surveillance through existing electronicanonymized patient-level registries available to healthcareprofessionals for consultation prior to an off-labelprescription of psychoactive drugs to children andadolescents

The lack of effective drugs for many childhood disorders Promote personalized psychopharmacology by: developing novel compounds to correct the underlying

pathophysiology in patients selected through geneticanalysis and biomarker panels

including longer follow-up periods testing drug behavioural treatment designs adopting scales with demonstrated pre-/post-treatment

sensitivityLack of evidence-based approaches to prevent psychiatricdisorders with adolescent-onset

Foster clinical trials on primary and secondary prev


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