Summary of main results

Overall, there was some evidence of limited efficacy of risperidone in reducing aggression and conduct problems in the short term in children and youths (aged five to 18 years) with disruptive behaviour disorders (four to 10 weeks), from a small number of studies in which there was some risk of bias of overestimating the true intervention effect. There were significant methodological limitations (Quality of the evidence), which impact on our confidence in the estimation of effect. There is no current evidence for the efficacy of quetiapine and ziprasidone on aggression and conduct problems in children and youths. Earlier studies did not include psychosocial interventions and stimulant medication treatments for comorbid ADHD in disruptive behaviour disorders. Recently, however, there has been some effort to address this in response to clinical guidelines and best clinical practice. So far there is only one trial which investigates the risperidone augmentation/combination with simultaneous stimulant medication and parent training in disruptive behavioural disorders. Risperidone treatment is associated with significant adverse events of weight gain and metabolic dysfunction.

For aggression, the difference in scores of 6.49 points on the ABC ‒ Irritability subscale (range 0 to 45) may be clinically significant. Owen 2009 used a difference of seven points on the ABC ‒ Irritability subscale as a measure of a clinically significant difference between treatment and placebo for children and adolescents with autistic disorder. Hassiotis 2009 used a difference of eight points on the ABC ‒ Irritability subscale between the treatment and control group to detect a clinically significant difference for challenging behaviour in adults with intellectual disabilities. The meaning of the differential findings on the two different ABS subscales is unclear. The scale splits aggression into two conceptually different constructs: reactive ("hot") and proactive ("cold"). From a clinical perspective, it can be difficult to distinguish between the two types of aggression. When we look at the risperidone‐only studies (Buitelaar 2001; TOSCA study), the differential findings on the two different ABS subscales remain, though the effect becomes larger and more precise as the heterogeneity of the meta‐analysis is reduced when we take out the quetiapine study (Connor 2008). In the future, we will consider pooling only risperidone studies.

For conduct problems, the difference in mean scores of 8.61 points on the NCBRF‐CP (range 0 to 48) is likely to be clinically significant. A difference of seven or more points on NCBRF‐CP by Reyes 2006a, and a difference of at least eight points on NCBRF‐CP by Tassé 1996, were considered to be clinically relevant differences between treatment and placebo in children and adolescents with disruptive behaviour disorders.

For weight gain, our meta‐analyses suggest a range in the average differences in weight gain from 2.14 kg to 2.37 kg over the treatment period, depending on whether there was concomitant administration of stimulant medication, which acts as an appetite suppressant. While weight is well documented, other metabolic side effects — including hyperprolactinaemia — were not well studied in the trials. However, these still need to be factored in clinically, as part of the risk benefit consideration.

Please refer to summary of findings Table for the main comparison.

Overall completeness and applicability of evidence

Ten RCTs assessed the efficacy of atypical antipsychotics in disruptive behaviour disorders in children and youths. Of these, eight trials assessed risperidone, one assessed quetiapine and one assessed ziprasidone. There were no RCTs in disruptive behavioural disorders for olanzapine, aripiprazole and the other newer atypical antipsychotics. Of the eight risperidone studies, three were pilot trials. One was a pilot trial of risperidone augmentation for treatment‐resistant aggression in ADHD (Armenteros 2007); one was a study of risperidone in the treatment of conduct disorder (Findling 2000); and one was a pilot trial of risperidone in the treatment of behavioural disturbances in children and youths in residential care with borderline intellectual functioning (Van Bellinghen 2001). The quetiapine trial was a pilot study of quetiapine in the treatment of conduct disorder (Connor 2008). The ziprasidone trial was also a pilot study of ziprasidone in the treatment of severe conduct disorder/disruptive behaviour disorders in children and youths (Fleischhaker 2011). Thus out of the 10 included trials, five are pilot trials, which has implications in terms of number of participants per trial.

There were small numbers of participants in five trials (38 participants or fewer) (Findling 2000; Buitelaar 2001; Van Bellinghen 2001; Armenteros 2007; Connor 2008). This had a significant impact on the power of the studies and the precision of the estimate of the effect. One trial had 50 participants (Fleischhaker 2011); two trials had over 100 participants each (Aman 2002; Snyder 2002); one had 168 participants (TOSCA study); and one had over 300 participants (Reyes 2006a). Participants in the trials were between five and 18 years of age. There were no data for children under five years. The study on quetiapine (Connor 2008), which had a small sample size and was inadequately powered, produced a non‐significant result for aggression. The study on ziprasidone was also underpowered and found no significant effect of the active agent (ziprasidone) compared with the placebo group at the end of treatment (Fleischhaker 2011).

Aman 2002 and Snyder 2002 were larger, outpatient, multicentre, randomised, double‐blind controlled trials of risperidone and placebo in children and youths with disruptive behaviour disorders and sub‐average IQ. Buitelaar 2001 was a randomised, double‐blind controlled trial of risperidone and placebo in inpatient youths with disruptive behaviour disorders and an IQ between 60 and 90. The TOSCA study was a large, multicentre trial. It had a complex study design with three treatment components and may be viewed as an augmentation study or a combination treatment study. What is important about the trial design in terms of the findings is that it sought to replicate ideal clinical treatment in the trial, with all participants already receiving stimulants for ADHD and parent training before the addition of risperidone.

Nine trials focused on acute efficacy (Findling 2000; Buitelaar 2001; Van Bellinghen 2001; Aman 2002; Snyder 2002; Armenteros 2007; Connor 2008, Fleischhaker 2011; TOSCA study), with the duration of intervention at four, six and 10 weeks. The tenth study was a six‐month maintenance trial looking at 'time‐to‐symptom' recurrence (Reyes 2006a). The duration of a RCT is an important consideration given the episodic nature of aggression, the natural waxing and waning of conduct problems, and the stability and the chronicity of the diagnosis of disruptive behaviour disorder, and in particular of conduct disorder (Steiner 1997; Steiner 2007; Connor 2008). Thus far, the follow‐up period in the trials is not long enough to demonstrate whether or not there is a sustained effect. We await the publication of the follow‐up results from the TOSCA study.

Due to the short duration of treatment in most trials there was a focus on short‐term adverse events. Earlier trials focused on weight gain, extrapyramidal side effects and prolactin levels. Metabolic side effects were poorly addressed in earlier trials; they were better documented in later trials (TOSCA study). Some trials continued as open‐label studies looking at safety, tolerability and continuation of effects of risperidone, but they were outside the parameters of this review. The long‐term, open‐label studies of risperidone in children with disruptive behaviour disorders were Turgay 2002, Croonenberghs 2005, Findling 2006 and Haas 2008, with up to one year's follow‐up; and Reyes 2006b, with up to three years' follow‐up.

Seven trials — Findling 2000, Buitelaar 2001, Aman 2002, Snyder 2002, Reyes 2006a, Connor 2008, and the TOSCA study — focused on a DSM‐IV diagnosis of a disruptive behaviour disorder with comorbid ADHD (American Psychiatric Association 2000); one trial focused on treatment‐resistant aggression in ADHD (Armenteros 2007); one trial measured behavioural symptoms instead of diagnoses (Van Bellinghen 2001); and one trial focused on primary DSM‐IV diagnoses of conduct disorder, oppositional defiant disorder and disruptive behaviour disorder not otherwise specified (Fleischhaker 2011). Trials that used DSM‐IV diagnoses would be more applicable clinically. The majority of the trials included participants with moderate‐to‐severe symptom severity and of clinical concern. This reflected clinical practice and circumstances where medication was warranted.

Seven trials included a significant number of participants with sub‐average to borderline IQ (range 36 to 84) (Findling 2000; Buitelaar 2001; Van Bellinghen 2001; Aman 2002; Snyder 2002; Reyes 2006a; Fleischhaker 2011), and only two trials, Reyes 2006a and Fleischhaker 2011, provided information on numbers, with approximately two‐thirds of participants having an IQ greater than 84 and IQ greater than 55, respectively. Armenteros 2007, Connor 2008 and the TOSCA study specifically excluded participants with sub‐average IQ. Thus the studies represented a mixed sample. In clinical practice, disruptive behavioural disorders are found in children and youths with both sub‐average and normal IQ and so the sample from the reviewed trials appears to be generalisable to the ones encountered in a clinical context.

With regards to the setting: eight studies were conducted with an outpatient population; one study looked at children in residential care (Van Bellinghen 2001); and one was carried out with inpatients (Buitelaar 2001). Outpatient management would be the most common in clinical practice and some children and youths with intellectual disability/mental retardation may be in residential care.

An important limitation in the evidence base was that earlier trials did not address the issue of pre‐existing or concurrent use of psychosocial treatments for disruptive behaviour disorders with medications, which is applicable in clinical practice. In one trial (Buitelaar 2001), it was specified that the participants had previously failed psychosocial treatment (contingency management and social skills training) before starting intervention with antipsychotic medication. Aman 2002 permitted behavioural therapy if it had started 30 days before the trial. Armenteros 2007 and Connor 2008 allowed "pre‐existing or current psychosocial interventions". The remaining trials did not comment on psychosocial interventions. There was no information in any of the trials about how many participants actually had concomitant psychosocial treatments and no further details of those treatments were described. This limitation was addressed directly by the TOSCA study, where all parents received evidence‐based parent training with monitoring of fidelity. This reflects ideal, optimal clinical treatment and the implication is that future clinical trials should incorporate psychosocial treatment into their designs.

Another limitation of the evidence was the comorbid treatment of ADHD with stimulant medication. There was no information available in earlier papers on the doses of stimulant medications used by participants: this was addressed by the TOSCA study to some extent. From baseline, there was a three‐week, open‐label, stimulant titration followed by six weeks of a double‐blinded, placebo‐controlled comparison of added risperidone versus placebo. Blader 2014 critiqued the three‐week duration of the pre‐treatment as not being long enough to establish an optimal stimulant regime. In the Blader 2013 study of adjunctive sodium valproate for ADHD children with aggression, the stimulant dosing took five to seven weeks or longer (alongside behaviour therapy) and, consequently, at least half the patients (82 out of 160 patients) showed remission of their aggressive behaviour. This compares with eight out 138 patients in the TOSCA study trial who responded to stimulants in the lead‐in phase. Blader 2014 also noted that adherence to stimulant treatment was not specifically addressed in the TOSCA study trial. ADHD symptom outcome was reported in a secondary paper (Gadow 2014).

Quality of the evidence

Important methodological limitations were present in the trials included in this review. Some of the trials were carried out pre‐CONSORT statement of 2001 (Moher 2001), thus the level of reporting currently expected was not available in the papers describing these studies, particularly with regard to the allocation concealment, randomisation and blinding processes. Fleischhaker 2011 did not follow the CONSORT standards. Reyes 2006a reported that they were unable to exclude the possibility of selection bias as only patients who responded to the initial acute treatment were subsequently randomised. No protocol was available for any of the trials. Three of the eight trials implemented a one‐week placebo run‐in to exclude placebo responders (Aman 2002; Snyder 2002; Connor 2008). One critique of this design was that placebo washout causes artificial inflation of the numbers apparently responding to the active drug and reduction of the numbers apparently responding to placebo (Jackson 2005, cited in Timimi 2008).

The overall attrition rate was relatively high, varying between 0% and 40% in the intervention group and 0% and 70% in the control group. This group of participants is difficult to study as, by definition, children and youths with disruptive behaviour disorders may not adhere to the rules of the treatment and research protocol; they may be oppositional and may not come for follow‐up appointments, and they may be itinerant. Therefore high dropout rates may be expected.

There were shortcomings in dealing with incomplete outcome data, in particular the use of the last observation carried forward as an imputation method to address incomplete data (Buitelaar 2001; Aman 2002; Snyder 2002; Reyes 2006a; Armenteros 2007). Criticisms against this method are that it is based on the underlying assumption that an individual’s missing value has not changed from the previously measured value and that it fails to account for the uncertainty about missing values (Wood 2004; Sterne 2009) and risk, resulting in standard errors that are too small (Sterne 2009) or CIs that are too narrow (Higgins 2011a). On the other hand, a limitation of the TOSCA study is that the published data are based on analysis of those who completed the study only, and the sensitivity analyses are not available for comparison. The overall implication is a potential risk of attrition bias, which may lead to an overestimation of the effect size.

Another methodological shortcoming is that there are significant overlaps in theoretical construct and measurement of aggression and conduct problems (Jensen 2007a; Calles 2011). There are no current gold standard measures of aggression or conduct problems. One implication is that by using different measures and reporting standards, it is challenging to pool the results for the purpose of a meta‐analysis or to understand the results from a clinical perspective.

All earlier trials had some degree of pharmaceutical support or sponsorship. Fleischhaker 2011 was an investigator‐initiated trial, financially supported by a pharmaceutical company. One trial specifically stated that the authors analysed all the data and completed all the writing (Connor 2008). From email correspondence (Loy 2016a [pers comm], we learned that the TOSCA study originally requested a pharmaceutical company to sponsor the study medication. Due to lack of agreement over certain issues, this fell through, except for one trial site. Subsequently, the authors obtained funding from the National Institute of Mental Health (NIMH) to purchase the study medications (both stimulant and risperidone and placebo) from an independent pharmacy. Only one study site, from which approximately 50 participants were recruited, received medication sponsored by the pharmaceutical company. It is possible that the centre used pharmaceutical‐supplied medication for one or two participants only. There were 168 participants in the trial. The lead author's view from this trial was that the pharmaceutical involvement was virtually nonexistent. There was no information available regarding this for the remainder of the trials.

For each trial included in the review, there were some areas of unclear bias and these are listed in the 'Risk of bias' tables, beneath the Characteristics of included studies tables. The overall quality of four trials was better than the others (Aman 2002; Snyder 2002; Reyes 2006a; TOSCA study), due to these trials being adequately powered and more methodologically rigorous, and therefore more trustworthy. Overall, we graded the quality of evidence as low, with the exception of the TOSCA study (Figure 3). Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate, given all the study limitations as well as methodological shortcomings. These are also listed in summary of findings Table for the main comparison.

Potential biases in the review process

We conducted a comprehensive review of published literature from databases and trial registers and extracted and synthesized the available information. However, we cannot be confident about the grey literature. We acknowledged the authors who replied to our queries for further clarification in the original review (Loy 2012); and acknowledge those who replied in this update (see Acknowledgements). There were authors who did not reply to our requests for further information and, therefore, we had to classify some aspects of the trials as 'unclear' especially with regards to methodological issues. This has an impact on our 'Risk of bias' assessment and GRADE assessment in terms of downgrading the evidence.

Agreements and disagreements with other studies or reviews

Differences to the previous version of this review, Loy 2012, include the addition of two new trials (one of which was published in a peer review journal (TOSCA study), and the other published as a conference poster (Fleischhaker 2011)); the synthesis of additional and combined data into one analysis; the discovery of two trials that were terminated at the recruitment stage and were never completed (one due to slow recruitment (NCT00279409), and the other due to drug formulation availability issues (ISRCTN95609637)); and recent updates in the literature.

Since the publication of our review in 2012 (Loy 2012), a number of new, clinical guidelines have been developed. The original guideline was the "TRAAY‐ Treatment recommendations for the use of antipsychotics for aggressive youth" (Pappadopulos 2003). Since 2012, the Treatment of Maladaptive Aggression in Youth (T‐MAY) Center for Education and Research on Mental Health Therapeutics (CERT) Guidlines I and II have been developed (Knapp 2012; Scotto Rosato 2012). Scotto Rosato 2012 recommended using evidence‐based, psychosocial interventions as the first line of treatment; targeting the underlying disorder first; considering individual psychosocial and medical factors in the selection of drugs, if evidence‐based medication treatment is initiated; avoiding the use of multiple, psychotropic medications simultaneously; and careful monitoring of treatment response by using structured rating scales, as well as careful monitoring for side effects.

Canadian guidelines on pharmacotherapy for disruptive and aggressive behaviour in children and adolescents with ADHD, oppositional defiant disorder and conduct disorder suggest that atypical antipsychotics are introduced only if psychosocial interventions have not shown adequate improvement (Gorman 2015). Risperidone received a conditional recommendation in this guideline due to risk of adverse effects. The results of this review are consistent with the role of risperidone given in these clinical guidelines. Only one trial in this review — the TOSCA study — closely resembles best, real world, clinical practice as outlined in the treatment recommendations.

A review by Pappadopulos 2006 reported a mean effect size of 0.9 for aggression for risperidone in treating disruptive behaviour disorders in children and adolescents. The studies in Pappadopulos 2006, which required effect‐size calculations for multiple raters, were averaged to determine the overall effect size. There were two duplications in this review as both Aman 2004 and LeBlanc 2005 were not stand‐alone studies but described post‐hoc analyses of the data from Aman 2002 and Snyder 2002 combined. The review also included some studies of children and youths with autistic spectrum disorder and disruptive behaviour disorders in the same analysis while autism spectrum disorder was not in our inclusion criteria. The effect size reported in Pappadopulos 2006 is large compared to the small effect size from our meta‐analysis for aggression for risperidone. The difference in our view is probably due to the inclusion of studies of children and youths with autistic spectrum disorder and comorbid disruptive behaviour disorders. Pappadopulos 2006 summarised and averaged the published effect sizes instead of conducting a meta‐analysis and this may have led to an overestimation of the effect size. The analysis by Jensen 2007b was similar to our review. There were six studies in the Jensen 2007b review with the exception of Armenteros 2007 and Connor 2008. Another issue was that the two reviews — Pappadopulos 2006 and Jensen 2007b — did not present CIs alongside the effect sizes. Since 2009, the sixth edition of the American Psychological Association's Publication Manual states that “estimates of appropriate effect sizes and confidence intervals are the minimum expectations” (American Psychological Association 2010, p 33).

Seida 2012 published a report called, "Antipsychotics for children and young adults: a comparative effectiveness review". This is a broad (non‐Cochrane) systematic review of the effectiveness and safety of first‐ (FGA) and second‐generation antipsychotics (SGA) for patients aged 24 years and younger with psychiatric and behavioural conditions. Because the authors focused on breadth, there is less depth in their analysis. A useful feature of this review is the authors' highlight of the number of studies looking at effectiveness (FGA versus SGA) and efficacy (drug versus placebo). They also identified the same eight studies for disruptive behaviour disorder. Their conclusion is that youths treated with risperidone had greater improvement on behavioural symptom measures and on CGI measures compared to placebo, with moderate strength of evidence. This is in contrast with our more conservative estimate of the effect.

Pringsheim 2012 reported a non‐Cochrane systematic review in December 2012, subsequent to our Cochrane Review, with the same eight trials and similar findings to ours. Duhig 2013 is a non‐Cochrane, non‐systematic review, specifically examining the efficacy of risperidone studies in children and adolescents with disruptive behavioural disorders. The authors cited the same seven trials of risperidone included in this review with similar findings. Pringsheim 2015 is a non‐Cochrane, systematic review of RCTs of antipsychotics, lithium and anticonvulsants. They included 11 RCTs of antipsychotics and seven RCTs of lithium and anticonvulsants. The authors concluded that there is "moderate quality evidence that risperidone has a moderate‐to‐large effect in conduct problems and aggression in youth with sub‐average IQ and ODD [oppositional defiant disorder], CD [conduct disorder] or DBD‐NOS [disruptive behaviour disorder ‐ not otherwise specified], with and without ADHD, and high‐quality evidence that risperidone has a moderate effect on disruptive and aggressive behaviour in youth with average IQ and ODD or CD, with or without ADHD". The authors also concluded that the evidence to support the use of antipsychotics and mood stabilizers is of low quality except for risperidone. Again, our findings are more conservative.

Our review does not include general expert opinion, commentary or partial reviews (Nevels 2010; Teixeira 2013b); or inpatient treatment of aggression in youths (Deshmukh 2010).

The TOSCA study group have published the results of their 12‐month naturalistic follow‐up (Gadow 2016), with an aim to report on the treatment regime, behavioural outcomes and adverse events. Following the nine‐week trial, blinded treatment of clinical responders continued until week 21 (Findling 2017). (Results were not available at the cut‐off date for this review, 19 January 2017, and therefore have not been included.) After week 21, study blind was broken and study staff assisted families to find ongoing care. According to the authors, after week 21, treatment was no longer free of charge to the families (Gadow 2016). At 12 months, there were 108 participants available for the follow‐up (basic = 55; augmented = 53), comprising 64% of the original sample. Of the participants, 43% in the augmented group and 36% in the basic group adhered to their assigned medication regimen; 23% in the augmented group and 11% in the basic group were not taking medications. About half of the participants were receiving modified drug treatment consisting of multiple drugs, including alpha agonists, selective serotonin reuptake inhibitors (SSRIs) and anti‐epileptics, in addition to stimulants and atypical antipsychotics in various permutations. While both treatment strategies were associated with clinical improvement at follow‐up, and primary behavioural outcomes did not differ significantly, parents still rated 45% of participants as impaired 'often or very often' from ADHD and as non‐compliant or aggressive. The authors raised issues of the impact of terminating parent training after week 21, and the impact of the unaffordability of the recommended treatment on long‐term outcomes (Gadow 2016).

It is important to note the theoretical concerns and themes in the literature regarding short‐ and long‐term side effects, and ultimately safety concerns for children and youth, to have a sense of the extent and depth of the problem (Devlin 2015). This will affect the risk‒benefit consideration and impact on decision on starting, adhering to, and persisting in treatment (Murphy 2015).

The weight gain reported in our review is of concern. It is unclear if the effect will attenuate over time. Correll 2009 suggests that interpretation of data may be hampered by variables prior to antipsychotic medication exposure, which can obscure cardiometabolic effects. In his prospective cohort study of weight and metabolic changes in paediatric patients naive to antipsychotic medication, 22.1% (60 participants) of the sample (272 participants) had disruptive or aggressive behaviour disorders. The rest had mood or schizophrenia spectrum disorders. After a median of 10.8 weeks of treatment, weight increased by 5.3 kg (95% CI 4.8 to 5.9 kg) in those treated with risperidone (135 participants). However, other authors of open‐label studies of risperidone for disruptive behaviour disorders in children and youth suggest that weight gain was greatest early on and levelled off between six and 12 months (Croonenberghs 2005, 504 participants; Turgay 2002, 77 participants) and two years (Reyes 2006b, 35 participants). About half of the mean weight gain of participants on risperidone at year one was attributable to developmentally expected growth (Turgay 2002; Findling 2004; Croonenberghs 2005).

In the 12‐month follow‐up of the TOSCA trial (Gadow 2016), the group exposed to risperidone treatment (augmented group) experienced an increase in weight from the end of acute treatment (week nine) till week 52, and weight gain was maintained at week 52, while the non‐exposed group (basic group) experienced decreased weight over time. Both groups had prior, concurrent stimulant treatment. The augmented group also had elevated prolactin levels (59%) compared to the basic group (5%) at 52 weeks (Gadow 2016). In a systematic review of cardiometabolic and endocrine side effects of atypical antipsychotics in children and adolescents, De Hert 2011 reported that risperidone was associated with intermediate weight gain (1.76 kg, 95% CI 1.27 to 2.25; 1200 participants).

Apart from weight gain, other cardiometabolic side effects like abdominal adiposity, hypertension, dyslipidaemia, insulin resistance and metabolic syndrome have been reported in children and youths treated with atypical antipsychotics (Devlin 2015). Recent estimates from longitudinal studies suggest that SGA‐treated children have a threefold greater risk of developing type 2 diabetes compared with untreated children. If there are problems of childhood obesity, it is associated with vascular damage in childhood, and with greater risk of cardiovascular disease in adulthood and at an earlier onset (Devlin 2015). Research into some genetic variants that may be useful in predicting cardiometabolic side effects in SGA‐treated children is still in its infancy (Devlin 2015).

It is known that risperidone can increase prolactin levels (Perkins 2004). One issue is that children may not have more common side effects of hyperprolactinaemia like galactorrhoea, amenorrhoea and sexual dysfunction. One concern is that hyperprolactinaemia at levels leading to hypogonadism may be associated with osteoporosis (Almandil 2011). Other (unconfirmed) potential risks from childhood hyperprolactinaemia are risk of breast cancer and pituitary tumours (Perkins 2004; Correll 2008). Little is known about the long‐term effects of risperidone treatment received early in the developmental course. In one animal study, adult rats treated with risperidone during development are hyperactive (Bardgett 2013). The authors queried whether chronic antipsychotic drug use in a paediatric population may modify brain development and alter neural set points for future specific behaviours.

Vitiello 2009 proposed that short‐term use of atypical antipsychotics includes a treatment course of less than six months, an intermediate treatment course of 18 months and long‐term use as beyond that. The authors' view is that distal benefit/risk ratio remains to be determined for long‐term treatment for atypical antipsychotics in general for children and adolescents. Caccia 2011 did a review on antipsychotic toxicology in children. The authors raised multiple, pertinent issues relating to further research on mechanisms underlying adverse effects, genetic risk of specific toxicities induced by antipsychotics and, because long‐term safety data are limited, advocated for permanent, systematic and collaborative epidemiological assessments and quantification for long‐term monitoring in this age group.

This challenge of a pharmacovigilance system has been taken up by the SENTIA (Safety of Neuroleptics in Infancy and Adolescence) project, which is an online monitoring registry in Spain (Palanca‐Maresca 2014). Another initiative, called the PERS (Pediatric European Risperidone Studies) project, plans to look at long‐term tolerability in a two‐year pharmacovigilance in children and adolescents with conduct disorder and normal intelligence (Glennon 2014).