European Neuropsychopharmacology (2015) 25, 1513–1531

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

nCorresponding aufax: +39 6 22541195

E-mail address: a

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REVIEW

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 Marañón, 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), Jörg 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 preventionusing pharmacological treatments either alone or as part of amultidisciplinary intervention

The need for better preclinical data to foster novel drugtherapies

Promote preclinical investigation especially in four areas,namely genetics, new animal models, induced pluripotentstem cells, and epigenetics including miRNAs and non-codingRNAs

Randomized clinical trials (RCTs) have methodologicallimitations and raise concerns, including:

Randomized clinical trials (RCTs) are the gold-standard inpaediatric psychopharmacology, but they can be amelioratedor alternatives can be applied, as follows:

� Limited generalizability due to sample selection criteria � Encourage phase III/IV trials targeting “real-life” patients(preschoolers, polypharmacy users, cases withcomorbidities, etc.)

� Overestimation of clinical benefits produced by the activedrug in an “artificial” experimental setting

� After a positive RCT, evaluate effectiveness in practicesettings (“large simple trials”)

� Inefficiency (expensive, time- and labour-consuming,vexed by high drop-out rates)

� Estimate dose– and time–response relationships byBayesian simulation and modelling of preclinical andclinical data; use interim data to modify the design in apre-planned manner (adaptive trial design); take measuresto minimize drop-out rates

� Enhanced risk of false-negatives due to high placebo effect � Reduce the number of recruiting sites, increase thenumber of cases recruited at each site, pay attention tothe geographic distribution of recruiting sites if ethnicdyshomogeneity in response to the active drug is likely,increase the duration of recruitment, reduce pressure byregulatory agencies to complete RCTs as soon as possibleregardless of study outcome

� Enhanced risk of false-negatives due to primary efficacyendpoints defined only by a significant decrease insymptom ratings below placebo, to reach a pre-establishedthreshold

� Also apply alternative endpoints (reduction in concomitantpsychopharmacological treatments, improved functionalmeasures and quality-of-life ratings, greater efficacy ofstandardized behavioural therapies); use scales andmeasures sensitive to change� Ethical concerns over using placebo in developing

individuals who may benefit from the active drug� Dose–response studies starting with a low drug dose and

without placebo� Add-on studies that assess the additional effect of a new

treatment in partial responders to standard therapy.

1515Unmet needs in paediatric psychopharmacology: Present scenario and future perspectives

Table 1 (continued )

Unmet needs Proposed solutions

� Enrolment of pathogenetically heterogeneous patients � Initially collect biomaterials and clinical data to lateridentify biomarker panels characteristic of responders;later recruit homogeneous subgroups of “probableresponders” based on biomarkers

Limited efficacy of current EU legislation on paediatric drugdevelopment

� Concerted efforts between regulatory agencies andindustry to agree upon incentives sufficient to foster(a) the clinical development of off-patent drugs and(b) the generation of adequate data, meeting criteria setforth by regulatory agencies

Growing resistance to treating children and adolescents withpsychotropic drugs in many patient families, medical doctorsand in society as a whole

� Develop drugs with unquestionable efficacy on currentlyuntreatable disorders

� Define sets of criteria for the establishment anddiscontinuation of drug treatment

� Acquire or expand currently-existing long-term efficacyand safety data

� Encourage widespread dissemination by reliable andauthoritative agencies, in objective ways and usingeffective vehicles, including web-based means

Table 2 Psychotropic medications approved in Europe for use in children and adolescents.

Medication Indication Age for prescription

Aripiprazole Schizophrenia Z15 yearsBipolar disorder, manic or mixed episodes Z13 years

Amphetamines (incl. Lisdexamphetamine) Attention-Deficit Hyperactivity Disordera Z6 yearsAtomoxetine Attention-Deficit Hyperactivity Disorder Z6 yearsFluoxetine Major depressive episode Z8 yearsFluvoxamine Obsessive–compulsive disorder Z8 yearsMethylphenidate Attention-Deficit Hyperactivity Disorder Z6 yearsRisperidone Aggressionb Z5 yearsSertraline Obsessive–compulsive disorder Z6 yearsZiprasidone Bipolar disorder, manic or mixed episodec Z10 years

aApproved only in some European countries for children and adolescents with ADHD.bApproved only in some European countries for children and adolescents with conduct disorder, in the presence of sub-average

intellectual functioning or intellectual disability and when all non-pharmacological strategies have been found insufficient.cApproved only in some European countries based on one randomized controlled trial (Findling et al., 2013), found by the US Food

and Drug Administration to have quality assurance issues, requiring the sponsor to repeat the trial.

A.M. Persico et al.1516

efficacy and safety in individuals younger than 18 years old,thus leading to their off-label use. In addition to age, alsothe origin and ethnicity of paediatric cohorts is relevant,because the European Medicine Agency (EMA), whileaccepting data generated outside the EU, requests that asizable percentage of paediatric patients be recruited inEurope. On the other hand, the patents of many of thesemedications have expired, leaving little commercial incen-tive for pharmaceutical companies to support the clinicaltrials necessary to achieve registration. These difficultiesare by no means limited to the EU, but are indeed presentalso in North America, so much that the Food and DrugAdministration (FDA) devised a 6-month patent extensionfor pharmaceutical companies providing long-term efficacy

and safety information for paediatric population. In the EU,it will be interesting to see in coming years whether and towhat extent the new EU Paediatric Regulation requiring aPaediatric Investigational Plan (PIP) for all newly marketeddrugs will overcome the paucity of information available inyouth and stimulate the achievement of more “PaediatricUse Marketing Authorizations” (see Section 7, for furtherdetails).

Meanwhile, during the last decade the rate of prescrip-tion of several psychotropic medications to children andadolescents has shown a dramatic increase both in the USA(Olfson et al., 2012, 2014) and also, albeit to a lesserextent, in several EU countries (Rani et al., 2008; Kalverdijket al., 2008). With the possible exception of

1517Unmet needs in paediatric psychopharmacology: Present scenario and future perspectives

psychostimulants, this increase in prescription rates per-tains mostly to the off-label use of second-generationantipsychotics (SGAs) or selective serotonin reuptake inhi-bitors (SSRIs) (Koelch et al., 2009). Country-specific prac-tices may underlie these trends: in Canada, prescriptions ofantipsychotics to youngsters (frequently off-label) are dis-proportionately higher among general practitioners thanamong psychiatrists (Murphy et al., 2013), whereas inGermany hospital-based specialists prescribe significantlymore antidepressants off-label compared to general practi-tioners (Dörks et al., 2013). Some data seemingly supportthis off-label use of SGAs and SSRIs in the paediatricpopulation for at least some indications, while also raisingcaution on their long-term effects:

(a)

SGAs. To date, only aripiprazole has received regulatoryapproval across all of Europe for paediatric indications,namely manic or mixed episodes of bipolar disorder inpatients 13–17 years old and schizophrenia in patients15–17 years old (Table 2). SGAs approved for paediatricuse in several, but not all European countries, includerisperidone for aggressive behaviour in patients aged 5–17 years with intellectual disability, and ziprasidone formanic or mixed episode of bipolar disorder in youthaged 10–17 years old. A review of 27 studies analyzedefficacy and/or tolerability of SGAs in children andadolescents with bipolar, autism spectrum or disruptivebehaviour disorders and indicated greater efficacy formania, extreme mood variability, irritability, aggressionand disruptive behaviour (mainly in patients with co-morbid intellectual disability or borderline IQ) (Zuddaset al., 2011) than in another review of 34 studies forpsychotic symptoms in schizophrenia (Fraguas et al.,2011). The average Number Needed to Treat (NNT) forstudy-defined treatment response was 2–5 for non-psychotic disorders, whereas for schizophrenia theNNT ranged from 3 for risperidone to 10 for olanzapine,quetiapine, and aripiprazole (Correll et al., 2011;Zuddas et al., 2011). As for schizophrenia, differentSGAs show similar efficacy also for non-psychotic dis-orders, but significantly differ in their tolerability andsafety profile (Correll et al., 2011; Zuddas et al., 2011).Acute adverse effects of SGAs in children and adoles-cents are usually minor, predictable and easily manage-able (Correll, 2008). However, some adverse events,such as drug-induced involuntary movements, meta-bolic, and endocrine side effects (i.e., hyperprolactine-mia and amenorrhea), occur more frequently inadolescents than in adults (Arango et al., 2014a). Inparticular, metabolic side effects, increasing the risk forcardiovascular disorders and for type 2 diabetes, may besevere and potentially life-span reducing (Correll et al.,2009; Arango et al., 2014a; Galling and Correll, 2015).Conversely, a clinical diagnosis of a psychotic disorder oreven isolated psychotic symptoms also significantlyincrease the risk of medical conditions (Moreno et al.,2013).

(b)

SSRIs. So far, only three SSRIs have received regulatoryapproval in Europe for use in the paediatric population:fluoxetine for moderate to severe major depressive epi-sodes starting at age 8, sertraline and fluvoxamine for

obsessive–compulsive disorder after age 6 and 8 (Table 1).No registration has been granted in the EU below age 18 forcitalopram, paroxetine, venlafaxine, and duloxetine,although many of these medications are used off-label inseveral western countries for mood disorders, anxiety,eating disorders and other behavioural disorders of childrenand adolescents. A recent survey carried out on the GermanPharmacoepidemiological Research Database (GePaRD),retrieving data from four German statutory health insur-ance companies, showed prescription rates of tricyclicantidepressants and SSRIs in 1.57–1.84/1000 children inthe years 2004–2006, with 49.1% of the prescriptions beingoff-label, more often for age than for indication (Dörkset al., 2013). Extensive meta-analyses have shown therelatively modest efficacy of all classes of antidepressants,including SSRIs, in juvenile depression, often related to ahigh placebo effect, particularly in prepubertal youth(Bridge et al., 2007; Qin et al., 2014). Potential explana-tions for these results include age-related differences in theneurobiological and psychosocial underpinnings of depres-sion and inadequate study design (i.e., inclusion criteria notsufficiently selective for severity or comorbidity, question-naires and outcome measures inappropriate for age, lack ofa placebo run-in phase before placebo randomization)(Moreno et al., 2007; Usala et al., 2008; Tsapakis et al.,2008). Importantly, in youngsters the efficacy of SSRIs issignificantly higher for obsessive–compulsive disorder (OCD)(NNT=6) and, especially, for generalized anxiety disorder(NNT=3) than for juvenile depression (NNT=10) (Bridgeet al., 2007), and very comparable to the efficacy recordedfor OCD and anxiety in adults (Huhn et al., 2014).

Not all off-label prescriptions are supported by sufficientevidence, which is very concerning. Both in the USA and in

Europe, prescription rates of SGAs to patients younger than18 years of age are significantly higher than the prevalenceof psychotic disorders (Rani et al., 2008; Kalverdijk et al.,2008; Zito et al., 2013). In fact, these medications are beingprescribed for aggression, irritability, negativistic and hos-tile behaviour in various conditions, such as autism spec-trum disorder, oppositional defiant disorder and conductdisorder (Olfson et al., 2012), when evidence of efficacy in“pure” conduct disorder (i.e., without co-morbid intellec-tual disability) is limited (Findling et al., 2000). Further-more, many psychiatric disorders in youth persist acrossdevelopment (Costello et al., 2011), requiring long-termdrug treatment. However, regardless of medication class,studies on maintenance treatments generating data on long-term efficacy and tolerability/safety are the exceptionrather than the rule in paediatric psychopharmacology,and recommendations for treatment type and duration afterthe acute phase are mostly derived from adult studies.

3. The lack of effective drugs for manychildhood disorders

No curative and only few symptomatically effective phar-macological agents are currently available for the treat-ment of psychiatric disorders with onset in childhood andadolescence. Disorders with the largest unmet needs wereidentified and prioritized by experts attending the TNMmeeting as displayed in Fig. 1, underscoring the critical

A.M. Persico et al.1518

importance of finding effective drug treatments especiallyfor autism spectrum disorder, bipolar disorder, anorexianervosa and other eating disorders, conduct disorder andfrequent cross-disorder conditions such as intellectual dis-ability, in addition to several others (see Fig. 1). This issue isof enormous relevance not only for affected youth and theirfamilies, but also for National Health Systems (NHSs),considering that most developmental disorders persist intoadulthood (Costello et al., 2011).

Autism spectrum disorder (ASD) was deemed by the expertsas the number one unmet need (Fig. 1). Effective pharmaco-logical treatments for the core symptoms of this severe andhighly impairing condition with childhood onset are indeed stilllacking. Despite considerable progress in understanding theneurobiology of ASD (Parellada et al., 2014), educational andbehavioural interventions still remain the only viable thera-peutic strategies able to variably ameliorate core autisticsymptoms, while pharmacological intervention has shownefficacy only on comorbid conditions or related symptoms(Politte et al., 2014). In particular: (a) psychostimulants havebeen proven effective in reducing the hyperactivity andimpulsivity, present in up to a third of ASD cases (Simonoffet al., 2008; Harfterkamp et al., 2012). Their efficacy issomewhat lower compared to effects in children with “pure”ADHD, while side effects (i.e., irritability, lethargy, tics,sadness, and social withdrawal) tend to be more frequentand severe in autistic children with comorbid ADHD (ResearchUnits on Paediatric Psychopharmacology Autism Network,2005; Simonoff et al., 2013); (b) SGAs, particularly risperidoneand aripiprazole, have been shown to control irritability,agitation, compulsions and aggressiveness, with evidence ofmaintained efficacy for up to 6 months of treatment in themajority of patients (Marcus et al., 2009; Politte andMcDougle, 2014; Zuddas et al., 2011); (c) SSRIs display someefficacy on anxiety and repetitive behaviours in adults, but notin children and adolescents with autism (Williams et al.,2010). This lack of efficacy in the paediatric ASD populationis likely related to age-specific differences in underlyingneurobiological mechanisms, to target symptoms (autisticindividuals report anxiety as distressing and stereotypic

Fig. 1 Priority order for drug development in child andadolescent psychiatry by disorder or condition. Each expertattending the ECNP Targeted Network Meeting was awardedthree priority options and ordinate values represent raw countsof disease priorities.

behaviours as relaxing), and to the use of assessment toolsand outcome measures that have been validated only inindividuals without ASD (Reiersen and Handen, 2011). Asevident from this brief summary, the core symptoms of ASDin children and adolescents (i.e., deficits in social interactionsand communication, stereotypic behaviours, insistence onsameness, abnormal sensory processing) still remain outsidethe direct targets of currently available pharmacologicalapproaches.

Despite the genetic complexity underlying ASD, the numberof pathophysiological processes involved in abnormal neuro-development being potentially amenable to pharmacologicalmodulation may be relatively limited (Persico and Napolioni,2013; De Rubeis et al., 2014; Pinto et al., 2014). To date, drugdevelopment strategies aimed at correcting the pathophysio-logical abnormalities underlying ASD have primarily taken themove from single-gene disorders that are frequently co-morbid with autism, ultimately leading to phase I-III studiesinitially aimed at treating the original single-gene disorder, butsubsequently or currently targeting ASD (Fig. 2). Experimentaltherapies relevant to ASD have been recently reviewed (seeTable 1 in Vorstman et al., 2014; also see Vitiello and Grabb,2013, and www.clinicaltrials.gov). Promising results in humanshave already been communicated for some of these drugs,when applied in cohorts of patients with ASD-associatedgenetic disorders (Franz et al., 2014; Jacquemont et al.,2011, 2014; Khwaja et al., 2014), whereas initial phase II/IIItrials performed to date in patients with ASD have failed tomeet their end-points (see Veenstra-VanderWeele et al., 2013,abs. 102.001; Kaufmann et al., 2013, abs. PS1-6). Thisdisappointing outcome may be attributable to several reasons,including (a) administration of a single experimental drug toheterogeneous groups of patients, regardless of their differentunderlying pathophysiology; (b) short trial durations; (c) lackof controlling for and/or associating specific behaviouralinterventions or rehabilitation programs; (d) using scales attimes not sufficiently sensitive to detect meaningful pre-/post-treatment change; and (e) treatment possibly outside ofthe critical period of maximum brain plasticity in the devel-opmental trajectory of the patient.

Patient (genetic syndrome)

Molecular modelsCellular modelsAnimal modelsChemical drug modellingBioinformatic analysis

Drug development

Patients (different syndromes, similar mechanisms)

Fig. 2 Translational approach to paediatric psychopharmacol-ogy, starting from the characterization of rare genetic syn-dromes and applying discoveries to more common and often co-morbid disorders (see text).

1519Unmet needs in paediatric psychopharmacology: Present scenario and future perspectives

A paradigmatic example of the challenges posed to experi-mental human psychopharmacology by ASD is represented bystudies investigating the use of antagonists at the metabotropicglutamate receptor type-5 (mGluR5). Approximately 50–67% ofboys and 20–23% of girls with Fragile-X syndrome (FraX) alsomeet diagnostic criteria for ASD as evidenced by well validatedinstruments (ADOS-G, ADI-R or both) (Clifford et al. 2007; Hallet al., 2008). FraX is due to the expansion of a CGG triplet-repeat located in the promoter of the FMR1 gene, whichproduces its methylation and transcriptional shut-down (Fuet al., 1991). The FMR protein (FMRP), encoded by the FMR1gene, negatively modulates translation locally at the synapticlevel by binding a variety of mRNAs and making them unavail-able to the translational machinery (Eberhart et al., 1996).Fmr1-ko mice were then shown to display abnormal long-termdepression due to excessive mGluR5 signaling and internaliza-tion of AMPA glutamate receptors: the “mGluR theory” of FraXthus lays the foundation of FraX pathophysiology upon threeconsequences of the absence of FMRP, namely: (a) excessivemGluR1/5 stimulation, (b) enhanced local protein synthesis,and (c) undue internalization of AMPA receptors (Bear et al.,2004). Indeed, a remarkable reversal of excessive proteinsynthesis, dendritic spine alterations and abnormal behaviouralphenotypes was observed in Fmr1-ko mice by blunting mGluR5signaling through genetic strategies (Dölen et al., 2007) or byadministering the mGluR1/5 antagonist MPEP (Yan et al., 2005;de Vrij et al., 2008). Despite this wealth of preclinical evidencestrongly supporting the promising efficacy of mGluR5 antago-nists in FraX and possibly in ASD, one preliminary clinical studyof an mGluR5 antagonist failed to reach its endpoints in adultFraX subjects, though showing some promise in the subgroup ofpatients carrying complete methylation of the FMR1 promoter(Jacquemont et al., 2011). Several explanations were putforward to explain the limited success of mGluR5 antagonistsin FraX, namely patient heterogeneity, lack of reliable markersto predict treatment response and side effects, outcomemeasures displaying low sensitivity to change, short trialduration and the use of a pharmacological intervention alonein the absence of a controlled behavioural treatment(Jacquemont et al., 2014). Particularly critical appears thenotion that if patient heterogeneity raises concern in studies ofa monogenic disorder like FraX, this concern is aggravated inpolygenic ASD. Further clinical studies with these medicationsare absolutely necessary before firm conclusions can be drawn,as the use of mGluR5 antagonists still represents a logical andscientifically-founded approach. Yet, based on initial trials,ongoing and future investigations will likely benefit fromselecting patients according to their underlying pathophysiol-ogy defined through biomarker panels, including longer follow-up periods, testing drug� behavioural treatment designs, andadopting scales with demonstrated pre-/post-treatment sensi-tivity (Jacquemont et al., 2014; Lee et al., 2014; Ruggeriet al., 2014).

4. In search for evidence-based approachesto prevent psychiatric disorders withadolescent-onset

Adolescence is a period of extraordinary physical, psycho-logical and social growth: personal and gender identity,morals and ideals, relationships with peers and adults, all

undergo major reshaping to finalize their developmentaltrajectory and form a fully “adult” self. Major hormonal andneurobiological changes underlie these phenomena: follow-ing overproduction of synapses during childhood, adoles-cence fosters the selection and stabilization of relevantsynaptic contacts, paralleled by prominent synapse elimina-tion under the influence of sex hormones. The number ofsynaptic contacts decreases by as much as 50% on averageat age 16 compared to early childhood (Huttenlocher, 1979).This synaptic remodelling profoundly affects neuronal cir-cuitry, especially in the prefrontal cortex, as well as theexcitatory/inhibitory neurochemical balance. Meanwhile,the completion of myelination finalizes the structural andfunctional connectivity underlying adult emotional andcognitive processing, including executive functions (workingmemory, self-regulation of affect-motivation-arousal, inter-nalization of speech, and behavioural analysis and synth-esis). Individuals vulnerable to disruptions of healthydevelopment are at special risk during this time: in fact,many adult psychiatric disorders become manifest by age 14and the large majority by age 24 (Kessler et al., 2005).The association with prenatal and perinatal hazards, thehigh frequency of minor neuro-motor abnormalities andphysical dysmorphisms, presence of minor structural brainabnormalities both predating and contemporary to theemergence of behavioural symptoms, and absence of neu-rodegeneration in post-mortem brains, all collectively sup-port the neurodevelopmental hypotheses put forth toexplain severe disorders with onset during adolescence orearly adulthood, such as schizophrenia (Arango et al., 2012,2014b). In brief, a general consensus currently views pre-and perinatal development as a critical period when genesand environmental factors can interact in vulnerable indi-viduals to produce functional and structural abnormalitiesthat often become evident only later during adolescence orearly adulthood. In the case of schizophrenia, differentgenetic pathways have been identified (SchizophreniaWorking Group of the Psychiatric Genomics Consortium,2014), while early social stress, drugs of abuse, inflamma-tion and oxidative stress appear to act as environmentalmodulators or triggers (Fraguas et al., 2012; Horváth andMirnics, 2015). The long latency between pre-/perinataldamage and the onset of behavioural abnormalities inadolescence spurs interest into primary prevention of thefull-blown disorder, provided reliable biomarkers of vulner-ability and early damage are established, as well as a betterunderstanding of pathogenic and resilience factors, as wellas their mutual interactions. Studies exploring the potentialefficacy of medications able to attenuate neuroinflamma-tion and oxidative stress in the CNS (e.g., glutathione, N-acetylcysteine, sulforaphane, polyunsatured fatty acids,glycine agonists, etc.) have yielded promising preliminaryresults in a wide variety of psychiatric and neurodevelop-mental disorders (Amminger et al., 2015; Chue and Lalonde,2014; Pandya et al., 2013; Singh et al., 2014).

The search for preventive strategies through pharmaco-logical therapy is not at all new in paediatric neurology andpsychiatry. An example of primary prevention is representedby magnesium sulfate administration to women at risk ofpreterm birth before 30 weeks’ gestation, where it has beenshown to significantly reduce the incidence of cerebral palsyand gross motor skill deficits in the offspring (Crowther

A.M. Persico et al.1520

et al., 2003). More often, psychopharmacological treatmentapplied early on, usually as part of a multidisciplinarytherapeutic intervention, has been shown to confer second-ary prevention by diminishing unfavourable developmentaltrajectories, otherwise leading to severe complications orto additional disorders. A consolidated example is ADHD as arisk factor for deviant behaviour (Barkley et al., 2004). In apopulation-based study, treatment with ADHD medications(methylphenidate, amphetamine, dexamphetamine or ato-moxetine) was shown to reduce criminality rates by as muchas 31% and 41% in convicted men and women, respectively,compared to unmedicated periods (Lichtenstein et al.,2012). Also relapse in substance abuse was reduced inaddicted criminal offenders undergoing methylphenidatetreatment (Konstenius et al., 2014). Similarly, methylphe-nidate treatment significantly reduces the risk of traumarequiring emergency department admission in ADHD (Manet al., 2015). Preventive opportunities are also offered bynovel medications such as everolimus, which seeminglyameliorates not only treatment-refractory epilepsy intuberous sclerosis, but also behaviour and quality-of-life(Krueger et al., 2013). Nonetheless the important area ofprimary prevention in schizophrenia is still in its initialstages, as only preliminary, but certainly not conclusiveevidence of effective preventive treatments has beenobtained so far (Correll et al., 2010).

5. The need for better preclinical data tofoster novel drug therapies

The importance of preclinical data in setting the stage forappropriately targeted and well-designed clinical trials hasclearly emerged in previous sections. Here, we shall focuson four specific approaches, namely genetics, animal mod-els, induced pluripotent stem cells (iPSC), and non-codingRNAs. Each represents a promising preclinical avenue forthe advancement of child psychopharmacology, but eachalso presents with limitations and caveats.

(A)

Human genetics represents one major foundation uponwhich drug discovery is being built through multipletranslational approaches. The past two decades haveseen a tremendous progress in understanding the geneticarchitecture of developmental psychopathology, whichinvolves both rare and common genetic variants. Thenumber of identified genetic variants associated withneuropsychiatric disorders has been rapidly increasing,both in terms of rare variants typically exerting a largeimpact on disease risk in few or even single patients, andof common variants, individually of small impact butcollectively of large effect on disease risk through thecumulative effect of many different variants in manyindividuals (Vorstman and Ophoff, 2013). Indeed, theproportion of patients with identified genetic abnormal-ities is currently estimated at approximately 20% in ASD(Jeste and Geschwind, 2014) and 40% in intellectualdisability (Topper et al., 2011), a substantial increasein comparison to the situation in the not-too-distantpast. Conversely, up to 30% of undiagnosed children withdevelopmental disorders can be correctly diagnosed by acombination of whole-exome sequencing and array-based

search for chromosomal rearrangements (TheDeciphering Developmental Disorders Study, 2015).Importantly, the increasing number of identified riskgenes appears to converge on a smaller number ofbiological pathways (Persico and Napolioni, 2013; DeRubeis et al., 2014; Pinto et al., 2014), thereby providingnovel insights into the underlying biology of thesedisorders. Examples include the mTOR pathway, chroma-tin regulation and synaptogenesis (Persico and Napolioni,2013; De Rubeis et al., 2014; Pinto et al., 2014; Vorstmanet al., 2014) in autism, neuronal migration in intellectualdisability (Liu, 2011) and glutamate signaling in ADHD(Elia et al., 2011). An important consequence of theseadvances is the possibility to identify potential novelpharmaceutical agents based on the growing insight intothe implicated biological pathways (Ghosh et al., 2013;Vorstman et al., 2014). In addition, as the number ofassociated risk variants continues to increase, the possi-bility of using individual genetic information as a meansof treatment stratification may become feasible. Forexample, a recent study has reported distinct neuronalbases of ADHD, depending on MAOA genotype (Nymberget al., 2013). Also, behavioural heterogeneity may bereduced when patients are stratified in accordance togenetic characteristics (Bruining et al., 2014). Possibly,the first clinical implementation of genetic stratificationstrategies may be their use in predicting treatmentresponse and/or adverse side effects of existing psycho-pharmacological treatments. Proof of principle has beenshown for several genotypes associated with, amongstothers, the risk of agranulocytosis in clozapine(Athanasiou et al., 2011) and the likelihood of antide-pressant treatment response to SSRIs in adults (Fabbriet al., 2014). Finally, going one step beyond genes intothe realm of developmental transcriptomics may allowthe definition of the critical periods of greatest diseaserisk and therapeutic sensitivity based on each individual’sunderlying genetics and neurobiology (Tebbenkampet al., 2014).Despite these perspectives, considerable challenges needto be resolved before insights from genetic studies canbe translated into useful applications in clinical practice:(a) genetic contributions to neurodevelopmental disor-ders remain elusive in the majority of patients; (b) forthe vast majority of currently identified genetic riskvariants, penetrance is far from complete and probablymodulated by other genetic variants (Leblond et al.,2012; Steinberg and Webber, 2013), as well as byepigenetic dysregulation dependent on parental age atconception and/or environmental factors (Berko et al.,2014; Frans et al., 2013; Persico and Merelli, 2014);(c) more than one biological pathway may be implicatedin single patients, thus possibly requiring drug combina-tions for targeted treatment; (d) many genetic riskvariants lack disease specificity, conferring vulnerabilitytoward a range of different neuropsychiatric and devel-opmental disorders (Smoller, 2013); (e) stratificationand/or prediction of treatment response of sufficientreliability likely require the use of genome-wide geno-type and CNV profiles, covering the entire spectrumof rare to common genetic and genomic variants, insteadof information derived from single genotypes. These

1521Unmet needs in paediatric psychopharmacology: Present scenario and future perspectives

challenges underscore the need to foster the parallelgrowth of knowledge into genetic and epigenetic variantsconferring disease vulnerability and of preclinical modelsable to summarize the functional derangements trig-gered by those variants.

(B)

Preclinical modelling plays a crucial role in fosteringsuccessful drug development. “Traditional” animal modelshave, on the one hand, provided a wealth of usefulneuroanatomical, neurochemical, electrophysiological,developmental and behavioural information; on the otherhand, limitations in face, construct and predictive validitymust be duly acknowledged, as they may in some caseshave contributed to the failure of some drug developmentprograms. Such failures may have occurred particularlywhen investigators have assumed animal models to repro-duce human disorders, rather than specific symptoms,traits or domains, or when human traits have beenprojected onto animals with insufficient considerationfor species-specificity (Kas et al., 2014). Confidence inpositive findings can be increased by the incorporation ofmultiple readouts of construct validity in the sameexperimental model. For example, optogenetics can becombined with oxygen biosensors and fMRI BOLD, which ismatched onto appropriate behavioural testing analogousto similar human tests (Kas et al., 2014; Weitz et al.,2015). Meanwhile, preclinical researchers should be readyto critically evaluate the validity of some long-held animalmodels, when positive findings in the animal model havenot resulted in equal success in clinical trials.

(C)

The last decade has seen the spurt of novel experimentalapproaches complementary to animal models, rangingfrom chemogenomic modelling (i.e., matching the targetprotein sequence with different chemical domains ofputative drugs) to bioinformatic tools capable of definingfunctional gene networks underlying complex behaviouraldisorders, as well as therapeutic drugs potentially able totarget those processes (Poelmans et al., 2011, 2013). Oneof the most promising experimental paradigm currentlyunder scrutiny employs induced pluripotent stem cells(iPSC) to model human disease (Kitchener and Wu, 2015):differentiated cells, such as fibroblasts or epithelial hairbulb cells, can be transformed into pluripotent stem cellsfollowing retrovirus-mediated transfection with the tran-scription factors c-Myc, Sox2, Oct 3/4, KLF4 (Yamanaka,2008). Subsequently iPSCs can be differentiated intospecific cell types of interest, including neurons. Alter-natively, differentiated cells can be reprogrammeddirectly into neurons by transfecting the four factorsAscl1, Brn2, Myt1l and NeuroD1 (Vierbuchen et al.,2010). The developmental and functional abnormalitiespresent in differentiated neurons in vitro are then pre-dicted to reflect the whole array of rare and commongenetic variants present in the patient’s genome, ratherthan the effect of a single mutation or CNV on a differentgenome. Once these abnormalities are clearly defined,iPSCs or iNEURONS can then be tested for responsivenessto specific psychoactive drugs. As an example, iPSC-derived neurons obtained from fibroblasts of patients withschizophrenia display decreased neurite number, reducedneuronal connectivity, and abnormal gene expressionrelated to glutamate receptors, cytoskeletal remodellingand oxidative stress; at least some of these parameters

respond to antipsychotic treatment (Brennand et al.,2012). Several experimental paradigms involving iPSC oriNEURON models of neurodevelopmental disorders havebeen published to date, underscoring the heuristic poten-tial of this approach (Krey et al., 2013; Cocks et al., 2014;Doers et al., 2014). Meanwhile, several major limitationsmust be duly acknowledged: (a) the most consistent andreliable transformation protocols have yet to be ulti-mately defined; (b) the entire process has low efficiency,is cumbersome, bears high costs and takes a long time;(c) the dysfunctional features observed in iPSC-derivedneuronal cells may partly be induced by the experimentalprocedure, which employs oncogenes as reprogrammingfactors, retroviral vectors for gene transfer and multiplemanipulations potentially capable of producing spuriousepigenetic abnormalities. Searching for anomalies alreadyin neural tube-like “rosettes”, which form as early as onculture day 15 (Lo Sardo et al., 2012; Harding et al.,2014), may represent an informative strategy for at leastsome neurodevelopmental disorders, while minimizingspurious effects due to later manipulations. Care mustbe taken, however, in the choice of in vitro readout usedto predict validity of test compounds in iPSC neurons andwhile a number of candidate assays are available, includ-ing electrophysiological and morphological changes, thereis presently little consensus on the ideal in vitro testbattery for drug screening.

(D)

Another promising area of investigation is represented bylong non-coding RNAs (van de Vondervoort et al., 2013;Meng et al., 2015) and especially by microRNAs (miRNAs),small non-coding RNA molecules essential for neuronalintegrity, as clearly exemplified by the progressive cere-bellar neurodegeneration and ataxia present in cell-specific dicer conditional knockout mice, unable to pro-duce miRNAs in Purkinje cells (Schaefer et al., 2007).MiRNAs are known to regulate multiple neurodevelopmen-tal processes and several miRNAs regulate the expressionof multiple genes relevant to neurodevelopmental disor-ders (Lett et al., 2013; Meza-Sosa et al., 2014). As anexample, miRNA 124 and 195 are both implicated inautism, each modulating multiple targets and thus affect-ing several autism genes (Vaishnavi et al., 2013). Finally,miRNAs are amenable to pharmacological modulationthrough drugs defined “antagomirs”, which can bind andantagonize miRNAs (Krützfeldt et al. 2005; Ghelani et al.,2012). Also long non-coding RNAs should be considered asa promising therapeutic target for specific neurodevelop-mental disorders (Meng et al., 2015). The inclusion ofsmall and long non-coding RNAs into computational mod-els is predicted to greatly enhance their capacity toexplain complex phenotypes, to point toward potentialtherapeutic avenues and to yield biomarkers that may beable to stand as surrogate end points in clinical trials.

6. Paediatric clinical trials: Methodologicalissues, problems and potential solutions

Randomized clinical trials (RCTs) have contributed remarkablyto paediatric psychopharmacology. We can now legitimately

A.M. Persico et al.1522

talk of evidence-based psychopharmacology for children andadolescents because dozens of RCTs have investigated thebenefits and tolerability/safety of various psychotropic medica-tions during development. While the epistemological value ofRCTs in paediatric psychopharmacology is undeniable, two maintypes of concerns have emerged over this experimental design:

(a)

The external validity of RCTs has been questioned,because sample selection and the experimental natureof the studies both limit the generalizability of theirresults. In simple terms, finding a statistically significantdifference between medication and placebo on a symptomrating scale after a few weeks of treatment in a researchsetting and in a highly selected sample of patients doesnot adequately inform about the therapeutic benefit ortolerability/safety of the medication when used underusual clinical conditions and for extended periods of time.Patient selection in RCTs is typically restricted to “pure”,uncomplicated cases, while “real-life” patients presentingwith polypharmacy, suicidal ideation, co-morbid intellec-tual disability or self-injurious behaviour, just to name afew, are typically excluded; they should instead representa “special-interest” group, worthy of targeted phase IVtrials, which are currently not required at all for labellingauthorization. Data collected in adults suggest that RCTsmay overestimate the effect size of clinical benefitsproduced by the active experimental drug, as comparedto observational studies (Naudet et al., 2011; Wisniewskiet al., 2009). This concern is not new, and it has beengenerally agreed that traditional RCTs, which establishinitial efficacy, should then be followed by practical trials(“large simple trials”), in order to evaluate effectivenessin practice settings (Geddes, 2005). However, few prac-tical trials have been conducted in paediatric psychophar-macology, primarily due to funding limitations and lack ofappropriate logistic infrastructure. In reference to age,preschoolers are clearly an understudied population;

(b)

The operative implementation of RCTs, as currently con-ducted, is burdened by a high perceived degree ofinefficiency. From an industrial perspective, RCTs areincreasingly expensive and extremely time- and labour-consuming. On the one hand, recruiting children andadolescents for double-blind placebo-controlled medica-tion trials has also become more difficult over time. On theother hand, RCTs are often marred by high drop-out rates.Sample sizes are thus often too small to provide thestatistical power needed to detect small- or evenmedium-size effects, which unfortunately represent thetypical outcome of pharmacological treatments in psychia-try (Huhn et al., 2014). Furthermore, placebo effects haveprogressively grown over the years often blunting treat-ment effects and making RCTs inconclusive. For example,recent studies failed to show separation from placebo onthe CDRS-R at 10 weeks for both the investigational drug(duloxetine) and the planned active control (fluoxetine)(Emslie et al., 2014; Atkinson et al., 2014). Importantly,one factor associated with high placebo response is thenumber of clinical sites involved in an RCT: the greater thenumber of sites, the larger the placebo response (Bridgeet al., 2009). Hence, increasing the number of recruitingsites, each providing only a few subjects, likely contributes

more error than valid information, decreasing rather thanincreasing experimental sensitivity despite larger samplesizes. Contrary to this notion, on average the number ofsites involved in RCTs has been progressively growing and itis not uncommon to encounter studies including more than60 recruiting sites, often spread across different countriesand continents (Atkinson et al., 2014). This trend is largelydue to regulatory pressure toward RCT completion as soonas possible regardless of study outcome, cost containmentand an attempt to maximize sparing of patent protectiontime by counteracting slow patient recruitment, especiallyfor conditions for which treatments are available in thecommunity, such as depression and anxiety. Not surpris-ingly, given these premises, most RCTs of antidepressantsin children and adolescents are failed or inconclusive trials.

Besides these two major concerns, other considerationsare also relevant to the development and testing ofpsychopharmacological treatments. Primary efficacy end-points in RCTs, typically represented by a statisticallysignificant decrease in symptom ratings compared to pla-cebo below a pre-established threshold, often oversimplifythe complexity of childhood psychiatric disorders andenhance the risk of false-negative results. Alternative end-points should be considered when regulatory agencies andpharmaceutical companies agree upon a paediatric investi-gational plan. For example, valuable endpoints for paedia-tric clinical trials, even in the absence of statisticallysignificant decreases in symptom scores, could well include:(i) a dosage decrease or discontinuation of concomitantpsychopharmacological treatments; (ii) consistentlyimproved functional measures and quality-of-life ratings;and (iii) more rapid and favourable improvements producedby standardized courses of behavioural therapies. Further-more, the targets of treatment are broad and not preciselydefined from a neurobiological point of view. Despiteremarkable advances in brain imaging, neurocognitiveassessment, molecular biology, human genetics and basicneuroscience, treatable psychiatric disorders still representheterogeneous categories defined only by behavioural symp-toms, in the absence of homogeneous neurobiologicalunderpinnings identifiable through valid biomarkers. Thislimitation affects RCTs at two levels: it leads to theenrollment of heterogeneous samples and to the assessmentof treatment effects through subjective rating scales. It isnot surprising that, under these circumstances, results aretoo often inconclusive.

For all of the reasons summarized above, though RCTs stillrepresent the gold standard method for demonstrating theefficacy of new medications, research into alternativemethodological approaches should be encouraged. Beloware some examples already in use:

a)

The use of placebo has been heavily debated in terms ofits real need and ethical acceptability. In general, theuse of a placebo-arm is considered ethically justifiablewhen needed to answer appropriate and necessaryscientific questions that cannot be answered in any otherway, and when risk for the patient is acceptable (Marchet al., 2004). There are, however, alternatives to the

1523Unmet needs in paediatric psychopharmacology: Present scenario and future perspectives

traditional placebo-controlled design, such as dose–response studies without a null dose (i.e., placebo) orwith a very low dose (i.e., faux or pseudo placebo), oradd-on studies that assess the additional effect of a newtreatment in partial responders to standard therapy(March et al., 2004). These designs could be moreacceptable to parents, facilitating children recruitment,and be more ethically justifiable especially in drug trialsof longer duration, where children entered into theplacebo arm could drop out or conceivably run the riskof growing out of a developmental stage of maximumtherapeutic responsiveness.

b)

Greater efficiency and cost-effectiveness can potentiallybe achieved through simulation and modelling of precli-nical and clinical data applying Bayesian methodologies toestimate dose–response and time–response relationshipsfor both drug efficacy and safety (Orloff et al., 2009).Adaptive trial designs make use of interim data to modifythe design in a pre-planned manner, without affecting itsvalidity and integrity (Orloff et al., 2009).

c)

Establishing efficacy of a new medication at the individualand group level may also be facilitated by incorporatingvalidated biomarkers into RCTs (Vorstman et al., 2014).This approach includes the need for stratification biomar-kers that indicate which patient groups may benefit from aparticular treatment; mechanistic biomarkers that reflectdifferences in underlying pathophysiology key to thedisorder, and substitute endpoint biomarkers that predictlater clinical response to drug treatment (Ruggeri et al.,2014; Loth et al., 2015). These biomarkers can be drawnfrom multiple levels ranging from basic biology (genomic,epigenomic, transcriptomic, proteomic, and metabolo-mics) to more complex levels closer to brain function(electrophysiology, brain imaging, eye tracking, neuropsy-chological testing, etc.). So far, few if any biomarkers havebeen validated and accepted by regulatory bodies forstudies in child and adolescent psychiatric disorders(Manolis et al., 2015). The Innovative Medicine Initiativeconsortium EU-AIMS (European Autism Interventions—AMulticentre Study for Developing New Medications, www.eu-aims.eu) has sought and obtained advice and guidancefrom the EMA to examine and validate eye-tracking,cognitive, EEG, MRI and biochemical biomarkers for thestudy of ASD (Loth et al., 2015).

In the meantime, existing electronic anonymized patient-level registries should be constantly enriched with clinicalrecords and monitored by healthcare professionals to amuch greater extent, in order to assist them with makingthe most appropriate therapeutic decisions when prescrib-ing off-label medicines in paediatric clinical practice.Relevant examples in Europe include:

�

The French multicenter prospective naturalistic study ofadverse events of antipsychotic treatment in naïve childrenand adolescents, funded by French National Agency forMedicines and Health Products Safety (Menard et al., 2014;id. NCT02007928 on www.clinicaltrials.gov);

�

SENTIA: a systematic online monitoring registry forchildren and adolescents treated with antipsychotics,

supported by the Spanish Ministry of Health and SocialPolitics (Palanca-Maresca et al., 2014);

�

The German large simple trial (phase IIIb) about the off-label use of antipsychotics and antidepressants, prospec-tive data collection by an internet-based patient regis-try, supported by the German Federal Institute of Drugsand Medical Devices (Egberts et al., 2015).

7. The regulatory context of paediatricpsychopharmacology in Europe: Strengths andlimitations

To address the need for more and better-quality clinical trialdata in paediatric medicine, a strategic plan was developedand a new EU Paediatric Regulation came into force in 2007(Regulations EC nos. 1901/2006 and 1902/2006, available athttp://www.ema.europa.eu/). On the one hand, pharmaceutical companies were legally obliged to perform studies inpaediatric patients if they intended to develop medicines foruse in the adult population, and to prepare a paediatric drugdevelopment plan, the “Paediatric Investigational Plan”(PIP). On the other hand, incentives were created for thepharmaceutical industry to test medicines in children andadolescents, namely a 6-month extension of the “Supplementary Protection Certificate” (SPC) including for adult use, anda 10-year extension of the “Paediatric Use Marketing Authorization” (PUMA) in the case that authorized products are nolonger covered by intellectual property rights. In parallel,the European Commission (EC) released in 2006 a documenton ethical considerations for clinical trials performed inchildren (available at http://ec.europa.eu/health/files/paediatrics/docs/paeds_ethics_consultation20060929_en.pdf).

The EU Paediatric Regulation has three main objectives:(1) to promote high quality research aimed at maximizingthe quality, safety and efficacy of medicines prescribed tochildren and adolescents, up to and including 17 years ofage; (2) to provide more information on the use ofpaediatric medicines, and (3) to allow the authorization ofmedicines for diseases that affect youth, with age-appropriate pharmaceutical forms and composition (formu-lation). As a positive result, in the period between 2007 and2012 the EMA and its Paediatric Committee have agreedwith pharmaceutical companies on more than 600 PIPs, toprovide data on the efficacy and safety of medicines for alldiseases of children and adolescents (European MedicinesAgency, 2013c). The proportion of RCTs involving youth hasincreased to approximately 10% of the total (EuropeanMedicines Agency, 2013a). To foster collaboration withinand outside the EU, the EMA has also created “PaediatricResearch Networks” (Enpr-EMA), involving the regulators,academia, the pharmaceutical industry, and patient asso-ciations (see below). Nonetheless, the fact that only onePUMA has been granted since 2008 indicates that thisregulatory context may still not provide adequate incen-tives to the industry for the clinical development of off-patent drugs (Schmäl et al., 2014).

Regulatory guidelines for the clinical investigation ofmedications for the treatment of psychiatric disorders suchas ADHD, schizophrenia and major depression have been

A.M. Persico et al.1524

issued by EMA, while guidelines for investigation of medica-tions for ASD are currently being developed (EuropeanMedicines Agency, 2010, 2012, 2013b, 2013c). For confirma-tory clinical trials, these guidelines specify at least tworandomized double-blind parallel-group design studies withgenerally three arms: the new target medication, placebo,and an active comparator. The duration of the trials shouldbe at least 6 weeks. In case of short-term efficacy, main-tenance of effect and long-term safety should be demon-strated in a randomized withdrawal design. Responders arerandomized to either continue treatment with the targetmedication or switch to placebo for at least 6 months.Responders are then further maintained on medication inopen-label fashion for a sufficient period of time, in order tocollect tolerability/safety data. An alternative for demon-strating long-term maintenance efficacy and safety is a 6-month randomized double-blind placebo-controlled parallelgroup study. If relevant, studies should be sufficientlypowered to allow for separate analyses of children (6–11year) and adolescents (12–18 year). The primary outcomemeasures should: (a) be based on clinicians’ ratings, com-plemented with ratings by significant others such as parentsand teachers, and whenever possible by self-reports, espe-cially in the case of adolescents, and (b) include not onlysymptom intensity scores, but also functional measures andquality-of-life ratings. The clinical investigation designsproposed in these guidelines present all the strengths andlimitations of RCTs discussed in the previous section.

8. Limited public acceptance of treatingchildren with medications

Until not too long ago, in many European countries thetreatment for child and adolescent psychiatric disorders waslargely confined to behavioural and psychosocial interven-tions. The use of psychotropic medications remained arelative rarity through the 1990s. Afterwards, a rapidincrease in prescription rates has occurred, especially formethylphenidate (Dalsgaard et al., 2013) and, to a lesserextent, for SGAs (Steinhausen, 2015; Olfson et al., 2012).Reservations around medication treatment for ADHD havebeen expressed both in society at large and within themedical profession for many years (Ruel and Hickey, 1992;Zwi et al., 2000). On a broader scale, treating children andadolescents with psychotropic drugs has encountered grow-ing resistance in many patient families and in society as awhole: the media have become increasingly critical aboutthe use of medications in children and adolescents, parti-cularly for psychiatric disorders (Thomas et al., 2013;Partridge et al., 2014); at least in some countries, parentstend to favour psychological treatments, cognitive training,or natural remedies (often not evidence-based) as a meansof “steering away from pharmacology” more than was thecase 10 years ago; society, media and even health profes-sionals, including many paediatricians, have become morecritical and cautious about medication effects on thedeveloping brain.

Several reasons may account for this changed apprecia-tion of medication treatment in child psychiatry. First, thesteep increase in prescription rates has led to worries ofpossible overdiagnosis and overtreatment, fuelled initially

by a purported lack of clear-cut boundaries between healthand disease in psychiatric disorders and, more recently, bythe introduction of DSM-5 (Batstra and Frances, 2012;Pierre, 2012). Second, this potential overtreatment hasbeen viewed by some as having been driven more bycommercial pressure from pharmaceutical companies thanby real medical need (Watson et al., 2014). Third, long-termtreatment duration is often not supported by sufficient dataon effectiveness and safety (Molina et al., 2009). In the caseof methylphenidate, there is only retrospective evidence ofeffectiveness beyond two years of long-term use (Barbaresiet al., 2014), but prescription in clinical practice oftenextends beyond this duration. Long-term methylphenidatetreatment has led to concerns about the risk of alteringchildren’s personality, but also about adverse effects onsleep, appetite and growth, as well as potential draw-backsregarding the nervous and cardiovascular systems (Gerlachet al., 2013; Germinario et al., 2013; Murray et al., 2013;Awudu and Besag, 2014; see ADDUCE project below). Lastly,these criticisms are often part of an ideological viewcentred around the concepts of ecology, sustainability,environmental concern and healthy natural remedies, ulti-mately purporting the damaging effects of anything “arti-ficial” or “man-made”on human health.

What lessons can be learned? As discussed above, theavailability of novel pharmacological agents not just effec-tive, but capable of “making the difference” in patients’lives is a critical point. Even today, the same parents whoare adamantly opposed to the prescription of psychotropicdrugs to their child for behavioural or psychiatric indica-tions, typically accept with ease the prescription of anti-epileptic drugs after a first convulsive episode, becauseepilepsy is perceived as a “severe disorder” and antiepilep-tic drugs are assumed to be very effective. Equally impor-tant is the acquisition of good quality data regarding long-term efficacy and tolerability/safety which may contributeto shift public opinion towards greater acceptability ofmedication treatments for children and adolescents withpsychiatric disorders. More attention should also be devotedto the development and implementation of monitoringguidelines for longer-term treatments, as typically appliedin clinical practice. Evidence-based guidance is also neededregarding when and how psychotropic medication should bediscontinued. Stopping strategies, as well as defining treat-ment refractoriness, are two somewhat neglected areas inthe field of child and adolescent psychiatry. Finally, alluseful drug-related information should be disseminated:(a) by reliable and authoritative agencies, (b) in objectiveways (i.e., steering away from both commercial interestsand ideological oppositions), and (c) reaching both patientsand prescribers also using popular and captivating vehicles,frequently web-based and close to current end-users.

9. European collaborative efforts and futuredirections

The issues and problems presented in each section of thisarticle need specific solutions, which require a solid andoverarching logistic infrastructure at the European level andbeyond, fostering intense collaboration among cliniciansand scientists with diverse cultural approaches, clinical

1525Unmet needs in paediatric psychopharmacology: Present scenario and future perspectives

background and pre-clinical expertise. This infrastructurecan then in turn implement innovative strategies to gen-erate and analyze large biological databases, and to trans-late innovation into clinical practice.

An initial stimulus toward the generation of this collabora-tive infrastructure was indirectly given by the PaediatricCommittee of the EMA, when a priority list of off-patentproducts was established for which studies were required inchildren and adolescents. This list then served as the basis forthe EU Seventh Framework Programme (FP7) communityfunding for research into off-patent medicines, object of itsfinal call. Three projects were funded to examine the use andtolerability/safety of psychotropic medications in children andadolescents: (a) PERS (Paediatric European Risperidone Stu-dies, www.pers-project.com), designed to assess the efficacyand long-term safety of risperidone in children and adoles-cents with conduct disorder and normal intellectual abilities(Glennon et al., 2014); (b) STOP (Suicidality: TreatmentOccurring in Paediatrics, www.stop-study.com), assessing andmonitoring medication-related suicidality in children andadolescents from three paediatric observational trials (risper-idone and aripiprazole in conduct disorder; fluoxetine indepression, and montelukast in asthma); and (c) ADDUCE(Attention-Deficit Hyperactivity Disorder Drugs Use ChronicEffects, www.adhd-adduce.org) investigating the neurological,psychiatric, auxological and cardiovascular adverse effects oflong-term methylphenidate administration in children andadults. Additional large-scale projects, also partially dealingwith psychopharmacology while addressing major topics inchild and adolescent psychopathology, were funded throughFP7, namely: (a) TACTICS (The “Translational Adolescent andChildhood Therapeutic Interventions in Compulsive Syn-dromes”, http://www.tactics-project.eu/), which intends toestablish predictive neural, genetic and molecular markers ofcompulsivity in paediatric populations, develop novel animalmodels to test pharmacological strategies against compulsivity,build translational biomarker databases and design future large-scale clinical trials accordingly; (b) AGGRESSOTYPE (“AggressionSubtyping for Improved Insight and Treatment Innovation inPsychiatric Disorders”, http://www.aggressotype.eu/), (c)FEM-NAT CD (“Neurobiology and Treatment of AdolescentFemale Conduct Disorder: The Central Role of Emotion Processing”, http://www.femnat-cd.eu/), (d) MATRICS (“Multidisciplinary Approaches to Translational Research In Conduct Syndromes”, http://matrics-project.eu/) and (e) ACTION (“Aggression in Children: unraveling gene-environment interplay toinform Treatment and InterventiON strategies”, http://ec.europa.eu/research/health/medical-research/brain-research/projects/action_en.html) programs, each including nested projects aimed at identifying neural, (epi)genetic and molecularfactors involved in the pathogenesis of aggression/antisocialbehaviour, in order to develop and pilot-test symptomatic andpreventive interventions in high-risk children with callousunemotional traits, and to identify innovative pharmacologicalinterventions for conduct disorder. These large academicstudies target a great deal of efficacy and tolerability/safetydata, with evidence of true real-world effectiveness.

The Child and Adolescent Neuropsychopharmacology Net-work, supported by the ECNP, has been instrumental inbuilding an infrastructure prompting several of the above-mentioned EU-funded projects. Additional centres havethen teamed up into a partly overlapping Enpr-EMA

European Child and Adolescent Clinical PsychopharmacologyNetwork, which also received support from the EuropeanNetwork for Hyperkinetic Disorders (Eunethydis), a foundingmember of the Enpr-EMA network which continues toactively participate as a member of the coordinatingcommittee. These centres have a solid track record inpaediatric psychopharmacology, assuring adequate experi-mental design, patient recruitment, biomarker definitionand clinical management in large-scale studies, includingformal RCTs for the registration of innovative medications.The existence of this pan-European infrastructure ensuresthat the translation of neurobiological discoveries intomuch-needed pharmacological therapies will be pursuedwith the greatest reliability and rapidity. The pace of thisprocess will also largely depend upon constructive legisla-tion and regulations, improving economies, funding priori-ties, dissemination campaigns able to effectively informpatients and their families while counteracting ideologicalopposition towards psychopharmacological interventions inchildren and adolescents. The treatment of psychiatricdisorders in youth and the prevention of their outburst inadolescents and adults represent two daunting, yet pivotaltasks, which well deserve every possible effort oneveryone’s part.

Role of the funding source

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

Contributors

Antonio M. Persico took notes during the TNM meeting, outlined thepaper’s content, contributed to writing the paper’s versions andcollated sections provided by co-authors. Celso Arango and Jan K.Buitelaar chaired the TNM meeting and contributed to the writingof the paper. Christoph U. Correll, Benedetto Vitiello, CarmenMoreno, Alessandro Zuddas, Pieter J. Hoekstra, Jacob Vorstman,and Jeffrey C. Glennon were either presenters or discussants at theTNM meeting, shared notes and slides, and contributed to thewriting of the paper. Two other members of the European Child andAdolescent Clinical Psychopharmacology Network, David Coghill andRalf W. Dittmann, provided detailed comments. All authorsapproved the final draft of the manuscript.

Conflict of interest statement

AMP, BV and JV have no conflict of interest to declare. CA has been aconsultant to or has received honoraria or grants from Abbot,AMGEN, AstraZeneca, Bristol-Myers Squibb, Caja Navarra, CIBER-SAM, 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 andSchering Plough. JKB has been in the past 3 years a consultant to/member of advisory board of/and/or speaker for Janssen Cilag BV,Eli Lilly, Shire, Lundbeck, Roche and Servier. He is not an employeeof any of these companies, and not a stock shareholder of any ofthese companies. He has no other financial or material support,including expert testimony, patents, royalties. CUC has been aconsultant and/or advisor to or has received honoraria from:AbbVie, Alkermes, Bristol-Myers Squibb, Eli Lilly, Genentech,

A.M. Persico et al.1526

Gerson Lehrman Group, IntraCellular Therapies, Janssen/J&J,Lundbeck, MedAvante, Medscape, Otsuka, Pfizer, ProPhase, Reviva,Roche, Sunovion, Supernus, and Takeda. He has received grantsupport from BMS, Otsuka, and Takeda. JCG has undertakenconsultancy work for Boehringer Ingelheim and is a formeremployee of Solvay Pharmaceuticals, but there is no conflict ofinterest to the topics presented in the current manuscript. PJH hasbeen paid member of advisory boards of Shire and Eli Lilly. CM hasbeen a consultant for Janssen-Cilag, Otsuka, AstraZeneca, Bristol-Myers Squibb, CIBERSAM, Instituto de Salud Carlos III, SpanishSpanish Ministry of Economy and Competitiveness, and FundaciónAlicia Koplowitz. AZ has received research grants or served asspeaker, adviser, or consultant for Otsuka, Lilly, Lundbeck, Shire andVifor Pharma.

Acknowledgments

The authors would like to acknowledge the other participants to theTNM meeting for helpful discussion. This work has been supportedby 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 Inno-vative Medicines Initiative Joint Undertaking under grant agree-ment no. 115300 (EU-AIMS), resources of which are composed offinancial contribution from the European Union’s Seventh Frame-work Programme (FP7/2007-2013) and the European Federation ofPharmaceutical Industries and Associations (EFPIA) companies’ inkind contribution. Additional support to AMP by the Italian Ministryof Health (CCM program 2012), the Fondazione Gaetano e MafaldaLuce, Autism Speaks and the Autism Research Institute; to AZ by theSardinian Regional Secretary of Health (Pharmacovigilance Res.Project); to CA and CM by the Spanish Ministry of Economy andCompetitiveness, Instituto de Salud Carlos III, CIBERSAM, MadridRegional Government (S2010/BMD-2422 AGES), European UnionStructural Funds, Fundación Alicia Koplowitz and Fundación MutuaMadrileña.

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