Effect of methylphenidate exposure on glutamate and glutamate-related metabolites in patients with ADHD: a systematic review

Background: Dysfunctional glutamatergic neurotransmission has been implicated in the underlying pathogenesis of Attention Deficit Hyperactivity Disorder (ADHD). The psychostimulant methylphenidate (MPH), which is used as a first line treatment for ADHD, has been shown to have both acute and chronic effects on prefrontal cortex glutamatergic afferents. Animal studies have also identified an effect of MPH and glutamate in prefrontal areas. Despite this there are ongoing questions as to the extent and direction of this effect, as well as its impact on other neurobiological processes. Methods: A systematic literature search was conducted following the PRISMA guidelines through the databases Embase, ScienceDirect and PubMed. Studies following pre/post and prospective designs were reviewed. Brain regions, metabolites of interest and phenotypical information were extracted from the relevant studies. Quality assessment tools of the National Heart, Lung, and Blood Institute were used to evaluate the risk of bias. Results: There were 10 studies that met criteria for inclusion. Three studies in children with ADHD identified a statistically significant decrease in glutamate level within fronto-cerebellar circuit and amygdala after MPH treatment. Most studies investigating adults with ADHD did not show a significant change in glutamate and glutamate-related metabolites after MPH exposure. Conclusion: A trend for decreased glutamate levels after MPH exposure were observed in studies involving children with ADHD. Future studies investigating the effects of MPH in children and adults with ADHD should utilise higher magnet field strength with larger sample sizes and over a longer duration of time with blinding and control group research design.