REVIEW
Unmet needs in paediatric psychopharmacology: Present scenario and future perspectives

https://doi.org/10.1016/j.euroneuro.2015.06.009Get rights and content

Abstract

Paediatric psychopharmacology holds great promise in two equally important areas of enormous biomedical and social impact, namely the treatment of behavioural abnormalities in children and adolescents, and the prevention of psychiatric disorders with adolescent- or adult-onset. Yet, in striking contrast, pharmacological treatment options presently available in child and adolescent psychiatry are dramatically limited. The most important currently unmet needs in paediatric psychopharmacology are: the frequent off-label prescription of medications to children and adolescents based exclusively on data from randomized controlled studies involving adult patients; the frequent lack of age-specific dose, long-term efficacy and tolerability/safety data; the lack of effective medications for many paediatric psychiatric disorders, most critically autism spectrum disorder; the scarcity and limitations of randomized placebo-controlled trials in paediatric psychopharmacology; the unexplored potential for the prevention of psychiatric disorders with adolescent- and adult-onset; the current lack of biomarkers to predict treatment response and severe adverse effects; the need for better preclinical data to foster the successful development of novel drug therapies; and the effective dissemination of evidence-based treatments to the general public, to better inform patients and families of the benefits and risks of pharmacological interventions during development. Priorities and strategies are proposed to overcome some of these limitations, including the European Child and Adolescent Clinical Psychopharmacology Network, as an overarching Pan-European infrastructure aimed at reliably carrying out much needed psychopharmacological trials in children and adolescents, in order to fill the identified gaps and improve overall outcomes.

Introduction

All theoretical frameworks to describe and analyse psychological functioning and human behaviour invariably view childhood and adolescence as crucial to the development of life-long mental health and disease. In recent decades, the growth of basic neuroscience has indeed pushed developmental psychology beyond limited descriptions and interpretations of human cognitive, emotional and behavioural trajectories, into a bio-psycho-social framework where the neurobiological underpinnings of typical development hold a key position (Lee et al., 2014, Schumann et al., 2014). Within this framework, the link between abnormal neurodevelopment and paediatric psychopathology has become the object of intense investigation, which holds a realistic promise to produce major advances in developmental neuropsychopharmacology in the not-so-distant future. Furthermore, adult psychiatric disorders have been shown to at least partly stem from neurodevelopmental abnormalities arising from early or late childhood, if not even prenatally (Salum et al., 2010).

Recognizing this great potential for major upcoming progress in clinical practice, but also acknowledging the serious limitations of current psychopharmacological interventions in paediatric neuropsychiatry, the Child & Adolescent Neuropsychopharmacology Network of the European College of Neuropsychopharmacology (ECNP; http://www.ecnp.eu/) held a Targeted Network Meeting (TNM) on October 4, 2013, satellite to the 26th Annual ECNP Congress (Barcelona, Spain). Thirteen experts presented evidence, shared opinions, described policies and debated views around the many unmet needs in child psychopharmacology. In the ensuing year, a dialogue on these subjects was continued by the participants with the goal of producing the present meeting report, which provides a snapshot of the most critical unmet needs, summarized in Table 1, as well as a general framework to guide future collaborative efforts and advance the field of paediatric psychopharmacology.

Section snippets

The off-label prescription to children and adolescents of medications with regulatory approval only in adults

Developmental neuropsychopharmacology has progressively evolved from considering youth as “small adults”, to investigating new fields of interest specific to children and adolescents (Arango, 2015). However, to date only very few medications have been approved in Europe for use in children and adolescents (Table 2). Many psychotropic medications prescribed to paediatric patients are unlicensed and off-label. In fact, the vast majority of medicines prescribed to children throughout the European

The lack of effective drugs for many childhood disorders

No curative and only few symptomatically effective pharmacological agents are currently available for the treatment of psychiatric disorders with onset in childhood and adolescence. Disorders with the largest unmet needs were identified and prioritized by experts attending the TNM meeting as displayed in Fig. 1, underscoring the critical importance of finding effective drug treatments especially for autism spectrum disorder, bipolar disorder, anorexia nervosa and other eating disorders, conduct

In search for evidence-based approaches to prevent psychiatric disorders with adolescent-onset

Adolescence is a period of extraordinary physical, psychological and social growth: personal and gender identity, morals and ideals, relationships with peers and adults, all undergo major reshaping to finalize their developmental trajectory and form a fully “adult” self. Major hormonal and neurobiological changes underlie these phenomena: following overproduction of synapses during childhood, adolescence fosters the selection and stabilization of relevant synaptic contacts, paralleled by

The need for better preclinical data to foster novel drug therapies

The importance of preclinical data in setting the stage for appropriately targeted and well-designed clinical trials has clearly emerged in previous sections. Here, we shall focus on four specific approaches, namely genetics, animal models, induced pluripotent stem cells (iPSC), and non-coding RNAs. Each represents a promising preclinical avenue for the advancement of child psychopharmacology, but each also presents with limitations and caveats.

  • (A)

    Human genetics represents one major foundation

Paediatric clinical trials: Methodological issues, problems and potential solutions

Randomized clinical trials (RCTs) have contributed remarkably to paediatric psychopharmacology. We can now legitimately talk of evidence-based psychopharmacology for children and adolescents because dozens of RCTs have investigated the benefits and tolerability/safety of various psychotropic medications during development. While the epistemological value of RCTs in paediatric psychopharmacology is undeniable, two main types of concerns have emerged over this experimental design:

  • (a)

    The external

The regulatory context of paediatric psychopharmacology in Europe: Strengths and limitations

To address the need for more and better-quality clinical trial data in paediatric medicine, a strategic plan was developed and a new EU Paediatric Regulation came into force in 2007 (Regulations EC nos. 1901/2006 and 1902/2006, available at http://www.ema.europa.eu/). On the one hand, pharmaceutical companies were legally obliged to perform studies in paediatric patients if they intended to develop medicines for use in the adult population, and to prepare a paediatric drug development plan, the

Limited public acceptance of treating children with medications

Until not too long ago, in many European countries the treatment for child and adolescent psychiatric disorders was largely confined to behavioural and psychosocial interventions. The use of psychotropic medications remained a relative rarity through the 1990s. Afterwards, a rapid increase in prescription rates has occurred, especially for methylphenidate (Dalsgaard et al., 2013) and, to a lesser extent, for SGAs (Steinhausen, 2015, Olfson et al., 2012). Reservations around medication treatment

European collaborative efforts and future directions

The issues and problems presented in each section of this article need specific solutions, which require a solid and overarching logistic infrastructure at the European level and beyond, fostering intense collaboration among clinicians and scientists with diverse cultural approaches, clinical background and pre-clinical expertise. This infrastructure can then in turn implement innovative strategies to generate and analyze large biological databases, and to translate innovation into clinical

Role of the funding source

None of the agencies which funded the authors had any role in the writing of this report and in the decision to submit the paper for publication.

Contributors

Antonio M. Persico took notes during the TNM meeting, outlined the paper’s content, contributed to writing the paper’s versions and collated sections provided by co-authors. Celso Arango and Jan K. Buitelaar chaired the TNM meeting and contributed to the writing of the paper. Christoph U. Correll, Benedetto Vitiello, Carmen Moreno, Alessandro Zuddas, Pieter J. Hoekstra, Jacob Vorstman, and Jeffrey C. Glennon were either presenters or discussants at the TNM meeting, shared notes and slides, and

Conflict of interest statement

AMP, BV and JV have no conflict of interest to declare. CA has been a consultant to or has received honoraria or grants from Abbot, AMGEN, AstraZeneca, Bristol-Myers Squibb, Caja Navarra, CIBERSAM, Fundación Alicia Koplowitz, Instituto de Salud Carlos III, Janssen Cilag, Lundbeck, Merck, Ministerio de Ciencia e Innovación, Ministerio de Sanidad, Ministerio de Economía y Competitividad, Mutua Madrileña, Otsuka, Pfizer, Roche, Servier, Shire, Takeda and Schering Plough. JKB has been in the past 3

Acknowledgments

The authors would like to acknowledge the other participants to the TNM meeting for helpful discussion. This work has been supported by the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement numbers 242959 (PERS), 278948 (TACTICS), 260576 (ADDUCE), 261411 (STOP), 603016 (MATRICS), and 602805 (AGGRESSOTYPE), 241909 (EU-GEI), 242114 (OPTiMISE), 603196 (PSYSCAN) and 602478 (METSY), and the Innovative Medicines Initiative Joint Undertaking under grant agreement

References (152)

  • M. Harfterkamp et al.

    A randomized double-blind study of atomoxetine versus placebo for attention-deficit/hyperactivity disorder symptoms in children with autism spectrum disorder

    J. Am. Acad. Child Adolesc. Psychiatry

    (2012)
  • S. Horváth et al.

    Schizophrenia as a disorder of molecular pathways

    Biol. Psychiatry

    (2015)
  • J.S. Liu

    Molecular genetics of neuronal migration disorders

    Curr. Neurol. Neurosci. Rep.

    (2011)
  • J. March et al.

    AACAP 2002 research forum: placebo and alternatives to placebo in randomized controlled trials in pediatric psychopharmacology

    J. Am. Acad. Child Adolesc. Psychiatry

    (2004)
  • R.N. Marcus et al.

    A placebo-controlled, fixed-dose study of aripiprazole in children and adolescents with irritability associated with autistic disorder

    J. Am. Acad. Child Adolesc. Psychiatry

    (2009)
  • B.S. Molina et al.

    The MTA at 8 years: prospective follow-up of children treated for combined-type ADHD in a multisite study

    J. Am. Acad. Child Adolesc. Psychiatry

    (2009)
  • C. Nymberg et al.

    Neural mechanisms of attention-deficit/hyperactivity disorder symptoms are stratified by MAOA genotype

    Biol. Psychiatry

    (2013)
  • G.P. Amminger et al.

    Predictors of treatment response in young people at ultra-high risk for psychosis who received long-chain omega-3 fatty acids

    Transl. Psychiatry

    (2015)
  • C. Arango et al.

    Progressive brain changes in children and adolescents with first-episode psychosis

    Arch. Gen. Psychiatry

    (2012)
  • C. Arango et al.

    Second-generation antipsychotics in children and adolescents: a six-month prospective cohort study in drug-naive patients

    J. Am. Acad. Child Adolesc. Psychiatry

    (2014)
  • C. Arango et al.

    Differential neurodevelopmental trajectories in patients with early-onset bipolar and schizophrenia disorders

    Schizophr. Bull.

    (2014)
  • M.C. Athanasiou et al.

    Candidate gene analysis identifies a polymorphism in HLA-DQB1 associated with clozapine-induced agranulocytosis

    J. Clin. Psychiatry

    (2011)
  • S.D. Atkinson et al.

    A double-blind efficacy and safety study of duloxetine flexible dosing in children and adolescents with major depressive disorder

    J. Child Adolesc. Psychopharmacol.

    (2014)
  • G.A. Awudu et al.

    Cardiovascular effects of methylphenidate, amphetamines and atomoxetine in the treatment of attention-deficit hyperactivity disorder: an update

    Drug Saf.

    (2014)
  • W.J. Barbaresi et al.

    Long-term stimulant medication treatment of attention-deficit/hyperactivity disorder: results from a population-based study

    J. Dev. Behav. Pediatr.

    (2014)
  • R.A. Barkley et al.

    Young adult follow-up of hyperactive children: antisocial activities and drug use

    J. Child Psychol. Psychiatry

    (2004)
  • L. Batstra et al.

    Diagnostic inflation: causes and a suggested cure

    J. Nerv. Ment. Dis.

    (2012)
  • E.R. Berko et al.

    Mosaic epigenetic dysregulation of ectodermal cells in autism spectrum disorder

    PLoS Genet.

    (2014)
  • K.J. Brennand et al.

    Modeling psychiatric disorders at the cellular and network levels

    Mol. Psychiatry

    (2012)
  • J.A. Bridge et al.

    Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials

    JAMA

    (2007)
  • J.A. Bridge et al.

    Placebo response in randomized controlled trials of antidepressants for pediatric major depressive disorder

    Am. J. Psychiatry

    (2009)
  • H. Bruining et al.

    Behavioral signatures related to genetic disorders in autism

    Mol. Autism

    (2014)
  • P. Chue et al.

    Addressing the unmet needs of patients with persistent negative symptoms of schizophrenia: emerging pharmacological treatment options

    Neuropsychiatr. Dis. Treat.

    (2014)
  • S. Clifford et al.

    Autism spectrum phenotype in males and females with fragile X full mutation and premutation

    J. Autism Dev. Disord.

    (2007)
  • G. Cocks et al.

    The utility of patient specific induced pluripotent stem cells for the modelling of Autistic Spectrum Disorders

    Psychopharmacology (Berl.)

    (2014)
  • S. Conroy et al.

    Survey of unlicensed and off label drug use in paediatric wards in European countries. European Network for Drug Investigation in Children

    BMJ

    (2000)
  • C.U. Correll et al.

    Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents

    JAMA

    (2009)
  • C.U. Correll et al.

    Research in people with psychosis risk syndrome: a review of the current evidence and future directions

    J. Child Psychol. Psychiatry

    (2010)
  • C.U. Correll et al.

    Developments in pediatric psychopharmacology: focus on stimulants, antidepressants, and antipsychotics

    J. Clin. Psychiatry

    (2011)
  • E.J. Costello et al.

    Trends in psychopathology across the adolescent years: what changes when children become adolescents, and when adolescents become adults?

    J. Child Psychol. Psychiatry

    (2011)
  • C.A. Crowther et al.

    Effect of magnesium sulfate given for neuroprotection before preterm birth: a randomized controlled trial

    JAMA

    (2003)
  • S. Dalsgaard et al.

    Five-fold increase in national prevalence rates of attention-deficit/hyperactivity disorder medications for children and adolescents with autism spectrum disorder, attention-deficit/hyperactivity disorder, and other psychiatric disorders: a Danish register-based study

    J. Child Adolesc. Psychopharmacol.

    (2013)
  • S. De Rubeis et al.

    Synaptic, transcriptional and chromatin genes disrupted in autism

    Nature

    (2014)
  • M.E. Doers et al.

    iPSC-derived forebrain neurons from FXS individuals show defects in initial neurite outgrowth

    Stem Cells Dev.

    (2014)
  • M. Dörks et al.

    Antidepressant drug use and off-label prescribing in children and adolescents in Germany: results from a large population-based cohort study

    Eur. Child Adolesc. Psychiatry

    (2013)
  • D.E. Eberhart et al.

    The fragile X mental retardation protein is a ribonucleoprotein containing both nuclear localization and nuclear export signals

    Hum. Mol. Genet.

    (1996)
  • K. Egberts et al.

    Pharmacovigilance in child and adolescent psychiatry

    Z. Kinder Jugendpsychiatr. Psychother.

    (2015)
  • J. Elia et al.

    Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder

    Nat. Genet.

    (2011)
  • G.J. Emslie et al.

    A double-blind efficacy and safety study of duloxetine fixed doses in children and adolescents with major depressive disorder

    J. Child Adolesc. Psychopharmacol.

    (2014)
  • European Medicines Agency, 2010. Committee for Medicinal Products for Human use (CHMP). Guideline on the Clinical...
  • Cited by (59)

    • The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present

      2021, Progress in Neuro-Psychopharmacology and Biological Psychiatry
      Citation Excerpt :

      These two systematic contributions, organized “by drug”, shall be followed by a third and conclusive article, aimed to provide an overview of available pharmacological options “by symptom”. The overarching aim of our effort is to help clinicians personalize the pharmacological therapies of their autistic patients, basing their prescription as much as possible on currently available scientific evidence, also considering that the vast majority of prescriptions of psychoactive drugs in child and adolescent neuropsychiatry occurs off-label (Persico et al., 2015; Sharma et al., 2016). The tremendous interindividual differences in ASD pathogenesis, clinical presentation and treatment response clearly imply that only evidence-based and individually tailored pharmacological therapies hold a real promise to improve the quality of life of autistic patients and of their family members.

    • Autisms

      2020, Neurodevelopmental Disorders: Comprehensive Developmental Neuroscience
    • Incidence of adverse events in antipsychotic-naïve children and adolescents treated with antipsychotic drugs: Results of a multicenter naturalistic study (ETAPE)

      2019, European Neuropsychopharmacology
      Citation Excerpt :

      For example, among children, metabolic monitoring is carried out about two times less frequently than in the adult population (Morrato et al., 2010). The medium and long-term consequences of many AEs are poorly known for the pediatric population and non-industry funded pharmacovigilance studies on the long term effects of SGA are lacking (Persico et al., 2015). Many countries have developed specific guidelines for the follow-up of AP treatments in children and adolescents (e.g. USA, Canada, United Kingdom and Spain, Raffin et al., 2014; Kendall et al., 2013; Ho et al., 2011), including clinical, physical and biological parameters.

    View all citing articles on Scopus
    View full text