Moderators and predictors of response to aripiprazole for tics in Tourette Disorder

Tourette disorder (TD) is a neuropsychiatric disorder (i.e., a condition characterized by clinically significant symptoms involving behaviors, emotions, cognitions, or brain functions such as language, movement, and memory, among others) characterized by several motor tics and at least one vocal tic with onset in childhood or adolescence and a duration longer than one year. Tics are movements (e.g., eye blinking, facial grimaces, head jerks) or sounds (e.g., sniffing, throat clearing) that are sudden, rapid, nonrhythmic, repetitive and involuntary. TD is relatively common in the general population, and currently available estimates indicate that 3-9 in 1000 children and young people live with this condition. Children and adolescents with TD experience distress and functional impairments because of tic-related interference in their physical, social, and academic lives. Some individuals with tics require intervention, and while behavioral treatments are generally recommended as first-line interventions, practitioners often resort to medications given the limited availability of trained therapists in the community.

To date, several pharmacological (drug) interventions have been tested in double-blinded randomized controlled trials (RCTs) (i.e., experimental scientific studies that enable testing the efficacy of proposed interventions with the highest level of credibility) for tics in TD. Antipsychotics (that is, a class of medication primarily used to treat psychosis where people see or hear things that are not there or believe things that are not true) are the most efficacious medications for tics in TD (ie., lead to the greatest reductions in tic symptom severity compared to placebo, ie., an inactive pill). Although the efficacy of different antipsychotics may be similar for TD, aripiprazole has been the most well studied antipsychotic for TD (both in number of RCTs and treated participants). Currently available scientific data indicate that the neurotransmitter (ie., chemical in the brain that carry messages through the nerves) dopamine may be implicated in the pathophysiology (i.e., the altered processes of typical human functioning that lead to health conditions) of TD and aripiprazole, as other antipsychotics, interfere with dopamine signaling in the brain.

Antipsychotics are associated with a poor safety profile, particularly in children and adolescents. Hence, practitioners are usually careful when prescribing these medications, and some guidelines recommend the use of other drugs with a smaller effect before trying antipsychotics.

Baseline characteristics (patient characteristics or symptoms observed before treatment) that can be used to predict a differential response to two treatments are called moderators. More generally, moderators are variables that influence the strength or direction of the relationship between a predictor (a variable used to estimate or explain an outcome) and an outcome. While predictors directly affect outcomes, moderators alter the way those effects vary across different conditions or subgroups. Identifying them is an important step to tailor recommendations in practitioners guidelines. In the case of TD, if we are able to identify individuals who are more (and less) likely to benefit from antipsychotics, practitioners may be more (and less) likely to prescribe them those medications.

Because individual RCTs are typically designed to detect the effect for a primary outcome considering all included participants, analyses to evaluate differences in subsets of participants based on only one RCT are of limited use since they do not include enough participants' data. Individual participant data (IPD) meta-analysis is a type of analysis which uses data from all the RCTs that are available and can address the insufficient statistical power (ie., the sensitivity to detect an effect) and ensure findings are generalizable (ie., findings are observed across all studies and not merely in one individual study).

In this study, we aim to fill this gap and conduct an IPD meta-analysis of RCTs of aripiprazole against placebo for TD. The resulting findings should help stratify current treatment recommendations for TD regarding the use of antipsychotics.