Twenty years of progress in paediatric psychopharmacology: accomplishments and unmet needs

Abstract

The systematic assessment of the efficacy and safety of psychiatric medications in children and adolescents started about 20 years ago. Since then, a considerable number of randomised clinical trials have been conducted, including also a series of publicly funded comparative effectiveness studies to evaluate the therapeutic benefit of medications relative to psychosocial interventions, alone or combined with medications. On the whole, these studies have been informative of the paediatric pharmacokinetics, efficacy and safety of the most commonly used psychotropics. As a consequence, a number of meta-analyses have been conducted that have documented both the benefits and harms of the most common medication groups, such as stimulants, antidepressants and antipsychotics. Evidence-based practice guidelines have been produced, and clinicians can now better estimate the therapeutic value and the risk of treatment, at least at the group mean level. However, most clinical trials have been conducted in research settings, and this limits the generalisability of the results. There is a need for evaluating treatment effects under usual practice conditions, through practical trials. The ongoing debate about the proper role of pharmacotherapy in child mental health can be advanced by comparative effectiveness research to assess the benefit/risk ratio of pharmacotherapy vis-à-vis alternative treatment modalities. In addition, analyses of large population databases can better inform on the impact of early treatment on important distal outcomes, such as interpersonal functioning, social and occupational status, quality of life and risk for disability or mortality. Thus far, paediatric psychopharmacology has been mostly the application to children of medications that were serendipitously discovered and developed for adults. By focusing on the neurobiological mechanisms of child psychopathology, it may be possible to identify more precise pharmacological targets and arrive at a truly developmental psychopharmacology.

Comparative efficacy and acceptability of antidepressants, psychotherapies, and their combination for acute treatment of children and adolescents with depressive disorder: a systematic review and network meta-analysis

“…We found that venlafaxine had a significantly increased risk for suicidality (suicidal behaviour or ideation) for young people, which is in line with previous reviews. 10,11 Two US medical claims databases that contain data on 221 028 young people with depression for the period 2004-09 showed that, after accounting for the time varying effect of confounders, the apparent association between antidepressant use and suicide attempts and selfinflicted injury was diminished and not statistically significant. 33 Antidepressant use by adolescents had previously been increasing but declined abruptly after the warnings were introduced.…”

“…7,8 The mean effects (standardised mean differ ence [SMD] -0•29) after treatment were more modest than those found for treatment of other youth problems, including anxiety (SMD -0•61), attention deficit hyper activity disorder (SMD -0•34), and conductrelated problems and disorders (SMD -0•46). 9 Previous metaanalyses 10,11 have shown that anti depres sants, except for fluoxetine, do not offer a clear advantage over pill placebo for many individuals, and some antidepressants might increase risk of suicidality. The mean effects of antidepressants for major depressive disorder compared with pill placebo (Hedges g 0•21 for selective serotonin reuptake inhibitor [SSRI] and 0•16 for serotonin-norepinephrine reuptake inhibitor [SNRI]) have been more modest than those found for treatment of other youth problems, including anxiety disorder (Hedges g 0•71 for SSRI and 0•41 for SNRI) and obsessivecompulsive disorder (Hedges g 0•39 for SSRI).…”

Antidepressants in Children and Adolescents: Meta-Review of Efficacy, Tolerability and Suicidality in Acute Treatment

“…The risk of bias and the quality of evidence of the individual studies varied and was assessed with different approaches across the included systematic reviews/meta-analyses. Even though randomised controlled trials are at the top of the hierarchy of evidence and have been used over the past 20 years to assess the effect of pharmacological interventions in children and adolescents ( 35 ), they may have limited generalizability and may be prone to sponsorship bias ( 36 ). Second, the overall quality of the systematic reviews retained in our meta-review, rated via the AMSTAR-2 tool ( 8 ), was variable, ranging from high for the network meta-analysis on ADHD ( 10 ) to critically low for the evidence synthesis on anxiety ( 11 ) and enuresis ( 14 ).…”

Celebrating the achievements of evidence-based child and adolescent mental health … and looking ahead to its continuous growth

“…In a comprehensive overview of the advances and challenges of child and adolescent psychopharmacology, Vitiello and Davico2 highlight how the past two decades of research in this area have been progressively shaped by the evidence-based approaches. Nevertheless, there is still a long way to move from symptom improvement to disease-modifying interventions, especially with relevance to treatment effects in usual practice conditions.…”

“…Nevertheless, there is still a long way to move from symptom improvement to disease-modifying interventions, especially with relevance to treatment effects in usual practice conditions. The review by Vitiello and Davico2 is also nicely completed by the paper authored by Baker and Carlson,3 who, after an extensive literature search, were able to identify only 10 studies using Pro Re Nata (PRNs) to manage agitated outbursts in children and adolescents in acute care settings and most were chart reviews. In fact, the only placebo-controlled trial of PRN medications was done by Vitiello and colleagues in 19904 which showed that placebo worked as well as active drug!…”