Drug safety and effectiveness in adults does not assure safety and effectiveness of the same drugs in children.
In the United States, >40% of systemic drugs ordered for children are off-label (used outside of an FDA-
approved age, indication, etc.). Furthermore, rates of off-label use in children are rising, particularly for
treatment indications unapproved at any age. Use, overuse, and combined use (polypharmacy) of off-label
medicines for unsupported indications may put millions of children at risk each year for serious drug-related
harms that outweigh uncertain benefits of treatment. This team’s long-term goal is to improve the judicious,
evidence-based use of medicines that will inform clinical decision-making and make children healthier and
safer. The specific objective of this project is to characterize the risks for serious drug-related harms in
children from some of the drugs used most commonly despite insufficient evidence of efficacy and safety:
psychotropic drugs. The central hypothesis is that use of certain psychotropic drugs in children is associated
with increased risks of serious harms. Psychotropic drugs are used as applied examples for many reasons: 1)
high and rising prevalence of unsupported off-label use in children; 2) insufficient evidence of efficacy in
children; 3) potential for serious or fatal harms; 4) potentially greater harms in children than in adults; 5) critical
therapeutic needs; 6) available therapeutic alternatives (e.g., safer drugs, non-pharmacologic interventions);
and 7) measurable outcomes. Based on these criteria, gaps in the literature, and preliminary data, this
proposal focuses on selected serious harms (namely, suicide, arrhythmias, and severe skin reactions) possibly
associated with antidepressants (e.g., venlafaxine) and antiepileptic drugs/mood stabilizers (AEDs) (e.g.,
lamotrigine). Specifically, this proposal aims to evaluate the extent to which: 1) certain antidepressants and
AEDs increase or decrease the risk of death by suicide in children (Aim 1); 2) certain antidepressants and
AEDs increase or decrease the risk of ventricular arrhythmias, cardiac arrest, or sudden death in children (Aim
2); and 3) certain antiepileptic drugs/mood stabilizers or drug combinations increase or decrease the risk of
severe skin reactions in children (Aim 3). The project team will study distinct pediatric populations within two
national claims and electronic health records databases to accomplish these aims. This research will produce
generalizable, actionable, clinically relevant evidence now lacking on relative and absolute risks of serious
harms from drugs and drug combinations increasingly used off-label and with insufficient evidence in children.
These rare outcomes cannot be feasibly studied with clinical trials due to the need for prohibitively large
sample sizes. Comparisons across age groups, diagnoses, drug doses, and concomitant drugs will not only
quantify risks in key subgroups but will also shed light on underlying biology and mechanisms. This project also
begins an important new line of work that will inform improvements the overall quality of evidence for drugs that
children commonly use despite insufficient evidence of efficacy and safety.
