Combination pharmacotherapy for psychiatric disorders in children and adolescents: prevalence, efficacy, risks and research needs

Polypharmacy, defined as the concomitant use of two or more psychotropic drugs, has become increasingly common in the paediatric and adolescent population over the past two decades. Combining psychotropic drugs leads to possible increases in benefits, but also in risks, particularly given the potential for psychotropic drug interactions. Despite the increasing use of concomitant therapy in children and adolescents, there is very little evidence from controlled clinical trials to provide guidance for prescribers. Even while acknowledging the small evidence base, clinical practice guidelines from eminent medical organizations are either relatively silent on or tend to support the use of concomitant treatments more enthusiastically than the evidence would warrant, so that practice and guidance are running ahead of the science. Our narrative review shows that the published evidence for efficacy and safety of concomitant psychotropic drugs in children and adolescents is scanty. A comprehensive search located 37 studies published over the last decade, of which 18 were randomized controlled trials (RCTs). These focused mainly on stimulants, central sympatholytics (such as clonidine), antipsychotics and 'mood stabilizers'. While several small, often methodologically weak, RCTs demonstrated statistically significant advantages for dual pharmacotherapy over monotherapy, only adding central sympatholytics to stimulants for treating attention-deficit hyperactivity disorder (ADHD) symptoms was supported by substantial studies with an effect size large enough to suggest clinical importance. Non-randomized studies tended to have results that supported concomitant treatment, but all have design-related problems that decrease the reliability of the results. Two studies that specifically examined tolerability of combination pharmacotherapy compared with monotherapy showed significant increases in adverse effects, both subjective and objective, and other studies confirmed a statistically significant increase in adverse effects, including sedation and self-harm. Given the extent of combination therapy occurring, particularly in conditions such as ADHD, and the ambiguous evidence for benefit with clear evidence of harm, we propose that further research should be carried out as a matter of urgency. Until such a time, the attitude to combination pharmacotherapy should be conservative, and combining psychotropic medications should be considered as an 'n of 1' trial to be closely monitored.Jon Jureidini, Anne Tonkin, Elsa Jureidin