REVIEWUnmet needs in paediatric psychopharmacology: Present scenario and future perspectives
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.
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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:
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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
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