Nocebo Effecten Verminderen in Kinderen Met ADHD: the NOVA Study

This is a randomized controlled clinical trial designed to investigate the impact of positively framed information (PFI) versus negatively framed information (NFI) on the reporting of adverse events (AEs) associated with the initiation of methylphenidate treatment in children with ADHD or ADD. The trial aims to evaluate whether the manner in which information about side effects is communicated can influence the prevalence, severity, and perception of those side effects, as well as parental satisfaction and medication adherence.

Study Rationale Attention Deficit Hyperactivity Disorder (ADHD) is a highly prevalent childhood condition, with a global prevalence estimated between 5% and 5.5% (Polanczyk et al., 2014). This condition is defined by two main symptom categories: inattention and motor restlessness/impulsivity. These symptoms profoundly affect various aspects of a child's daily functioning (Carucci et al., 2020). Management of ADHD generally involves an integrated strategy that combines both pharmacological and non-pharmacological interventions (van der Schans et al., 2017).

Pharmacological treatment with stimulants such as methylphenidate and (lis-)dexamfetamine has been demonstrated to be highly effective, significantly reducing symptoms as reported by children and observed by parents and teachers (Cortese S et al., 2018 & Elliott et al., 2020). However, these treatments are often accompanied by adverse events (Elliott et al., 2020), with decreased appetite, abdominal pain, headaches and sleep disturbances being the most common, which can significantly impact the quality of life (Graham J et al., 2008 & Graham J et al., 2011). Adverse events of these medication most commonly lead to non-adherence to therapy, potentially resulting in long-term negative outcomes such as an increased risk of criminal behavior, substance abuse or traffic accidents (Kamimura-Nishimura et al., 2019). Evidence indicates that approximately 50% of children and adolescents fail to adhere to their prescribed treatment (Hodgkins et al., 2011). Therefore, minimizing adverse events to im-prove adherence to ADHD therapy is crucial.

According to the World Health Organization (2003), adherence is influenced by multiple fac-tors, including patient characteristics, the medical condition, therapy, the healthcare system, and socioeconomic circumstances. One factor that possibly influences the experience of ad-verse events in adults is the patient's expectation of experiencing them (Whitford et al., 2012 & Prediger et al., 2019 & Morris et al., 1982), which is partly shaped by the information provid-ed by healthcare professionals. These unintended expectation-induced adverse events are known as nocebo effects (Colloca et al., 2020). Studies in adults have shown that adverse events are more likely to occur if they are discussed beforehand, especially if presented neg-atively (e.g., "5% of the patients experience nausea") versus positively (e.g., "95% of the pa-tients do not experience nausea" or "95% feel well") (Webster et al., 2018 & Faase et al., 2019 & Smith et al., 2020). Moreover, studies have demonstrated that patients report more side effects following placebo treatment compared to those who are untreated (Colloca et al., 2020 & Howick et al., 2018 & Jensen et al., 2012 & Rief et al., 2011). Based on these and other studies, an expert group on placebo and nocebo mechanisms advised doctors to present information on treatments in such a way that nocebo effects are minimized (Evers et al 2021).

Despite extensive research on the nocebo effect in adults, studies specifically targeting chil-dren are virtually nonexistent. This is surprising given that children are naturally more sug-gestible than adults are and may possibly respond more strongly to both positively and nega-tively framed suggestions. Recent questionnaire-based research at our outpatient clinic, St. Antonius Hospital in the Netherlands (de Bruijn et al., 2023), indicated that parents and teen-agers prefer to receive positive information about potential adverse events. However, whether this indeed results in fewer adverse events in children is still unknown.